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Review

Target Therapy for Hepatocellular Carcinoma: Beyond Receptor Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors

by
Hyunjung Park
†,
Hyerin Park
†,
Jiyeon Baek
†,
Hyuk Moon
and
Simon Weonsang Ro
*
Department of Genetics and Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si 17104, Korea
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Biology 2022, 11(4), 585; https://doi.org/10.3390/biology11040585
Submission received: 23 February 2022 / Revised: 19 March 2022 / Accepted: 7 April 2022 / Published: 12 April 2022
(This article belongs to the Special Issue Cancer Signaling Pathways, Crosstalk and Therapeutics)
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Abstract

:

Simple Summary

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and its incidence is steadily increasing. The development of HCC is a complex, multi-step process that is accompanied by alterations in multiple signaling cascades. Recent years have seen advancement in understanding molecular signaling pathways that play central roles in hepatocarcinogenesis. Aberrant activation of YAP/TAZ, Hedgehog, or Wnt/β-catenin signaling is frequently found in a subset of HCC patients. Targeting the signaling pathway via small molecule inhibitors could be a promising therapeutic option for the subset of patients. In this review, we will introduce the signaling pathways, discuss their roles in the development of HCC, and propose a therapeutic approach targeting the signaling pathways in the context of HCC.

Abstract

Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. To date, receptor tyrosine kinases (RTKs) are the most favored molecular targets for the treatment of HCC, followed by immune checkpoint regulators such as PD-1, PD-L1, and CTLA-4. With less than desirable clinical outcomes from RTK inhibitors as well as immune checkpoint inhibitors (ICI) so far, novel molecular target therapies have been proposed for HCC. In this review, we will introduce diverse molecular signaling pathways that are aberrantly activated in HCC, focusing on YAP/TAZ, Hedgehog, and Wnt/β-catenin signaling pathways, and discuss potential therapeutic strategies targeting the signaling pathways in HCC.

1. Introduction

The incidence of liver cancer has been steadily increasing, posing a major global health problem. The World Health Organization reported that about 800,000 deaths were due to liver cancer, making it the fourth leading cause of cancer-related death [1]. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, making up about 80% of the cases [2,3]. Surgical resection or local ablation therapy is performed for early-stage HCC, however, tumors recur in approximately 70% of these patients within 5 years [1,4]. Furthermore, although the diagnosis of HCC has improved significantly over past years, less than 30% of patients are diagnosed at the early stages when resection or local ablation is still available [1]. In the case of advanced HCC, systemic therapy is recommended as the standard treatment option, however, the prognosis has been unsatisfactory in general [1,2].
Molecular target therapy has been intensively studied in recent years as a promising treatment option for patients with advanced HCC [5,6,7]. The last decade has seen a significant advancement in molecular targeted therapy for HCC. Various small-molecule compounds targeting receptor tyrosine kinases (RTKs) have been tested in preclinical animal models and patients with HCC. So far, however, clinical outcomes of RTK-targeting molecular therapy have been less than satisfactory. For example, sorafenib is the leader compound among RTK inhibitors that are currently administered to patients with HCC, however, it has provided limited benefits for patients with HCC [7,8]. As a new therapeutic approach, immune checkpoint inhibitors have recently emerged a promising therapy for HCC [9,10,11,12,13]. Despite early excitements, targeting immune checkpoints alone has not shown prolonged therapeutic effects in HCC [8,9,13]. A combination of immune checkpoint inhibitors with other types of target therapy is currently considered most effective for the treatment of HCC and has been clinically tested.
Given the extreme heterogeneities in the molecular signature of HCC and difficulties in the development of globally-effective therapeutics for the disease, identification of molecular signaling pathways dysregulated in HCC would be fundamental to developing therapeutic targets as a personalized medical approach. In this review, we will introduce molecular signaling pathways beyond RTK that are aberrantly activated in HCC, that is, YAP/TAZ, Hedgehog, and Wnt/β-catenin signaling pathways, and discuss potential therapeutic strategies targeting the signaling pathways in the context of HCC.

2. Targeting YAP/TAZ in Liver Cancer

2.1. YAP/TAZ Signaling Pathway

YAP/TAZ signaling is majorly activated when a tumor-suppressive Hippo signaling pathway is inactivated. A variety of mechanical signals such as cell shape and extracellular matrix (ECM) stiffness, as well as cell–cell interactions, elicit signals regulating the Hippo signaling cascade [14,15,16]. The Hippo signaling is also regulated by modulation of cell adhesion and cell polarity [17,18].
The Hippo–YAP/TAZ signaling pathway consists of mammalian sterile 20-like kinase 1 (MST1; also known as STK4) and MST2 (also known as STK3), large tumor suppressor kinase 1 (LATS1) and LATS2, the adaptor proteins Salvador 1 (SAV1), MOB1A and MOB1B, and yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1, also known as TAZ) [19,20] (Figure 1). The signal from the receptor goes through neurofibromatosis 2 (NF2) to MST1/2 [6,19,21]. When MST1/2 is activated by NF2, MST1/2 forms a complex with SAV1 and phosphorylate LATS1/2 and MOB1. Phosphorylated LATS1/2 then leads to phosphorylation of YAP and TAZ (YAP/TAZ). Phosphorylated YAP/TAZ bind to 14-3-3, resulting in cytoplasmic sequestration of the transcription factors, or are ubiquitylated, leading to protein degradation via the ubiquitin–proteasome pathway [19,22]. In contrast, when the Hippo signaling is turned off, upstream components of the Hippo signaling pathway become unphosphorylated, and this allows YAP/TAZ to translocate into the nucleus and activate the transcription of their target genes through the interaction with the TEA domain family members (TEAD1–TEAD4) [21,22]. Hippo-YAP/TAZ signaling has a major role in the regulation of cell proliferation, apoptosis, migration and differentiation, all essential for both developmental processes and homeostasis in adult organs [6,23,24,25,26].

2.2. YAP/TAZ Signaling in Liver Cancer

YAP/TAZ signaling is involved in multiple facets of carcinogenesis, including the promotion of cellular proliferation, maintenance of cancer stem cells (CSCs), and induction of tissue invasion of tumor cells, as well as drug resistance and recurrence of cancer [16,27,28,29]. In human HCCs, approximately 60% showed elevated levels of YAP/TAZ expression [30,31,32]. Of note, patients with liver cancer showing YAP overexpression have significantly low survival rates and high tumor recurrence rates, compared with those showing low levels of YAP expression [30,33].
Human HCC cells with high YAP or TAZ levels exhibit poor differentiation [28,34]. Moreover, when knockdown of TAZ was performed in human HCC cell lines, they revealed substantial declines in cell proliferation, migration, and invasion capabilities [35,36]. In addition, epithelial-mesenchymal transition (EMT) marker genes such as N-cadherin, vimentin, and snail, were downregulated following the knockdown of TAZ, indicating that TAZ promotes EMT of HCC cells [35,36]. In line with TAZ knockdown, when YAP was knocked down in human HCC cell lines, migration and invasion were significantly diminished [37,38]. Cell lines with a high YAP/TAZ level showed high capabilities of metastasis, as well [36]. Overall, the reports suggest that YAP/TAZ can contribute to multiple facets of HCC pathogenesis.
In addition to the roles played by YAP/TAZ in cell proliferation, apoptosis and migration, YAP/TAZ are also involved in hepatic fibrosis. Considering significant correlations between hepatic fibrosis and liver cancer, it is noteworthy that YAP/TAZ could initiate and promote hepatocarcinogenesis via upregulation of stromal activation and hepatic fibrosis [24,26]. Finally, YAP/TAZ play important roles in regulating the tumor microenvironment, cell metabolism, etc. [24,26,39,40].

2.3. Animal Models of Liver Cancer Induced by Activated YAP/TAZ Signaling

The precise roles of the Hippo–YAP/TAZ signaling pathway in hepatocarcinogenesis have been studied using genetically engineered mouse models in which various components of the signaling cascade were deleted or activated (Table 1). The studies consistently show that the inactivation of the Hippo signaling pathway increased YAP/TAZ activities, leading to liver overgrowth and ultimately the development of liver cancer [26,41,42].
Liver-specific deletion of NF2 using NF2flox/flox mice and AAV-CRE (that is, CRE-expressing adeno-associated virus) led to the elevation of YAP/TAZ levels in the liver [45]. In NF2 knockout models, the proliferation of cells in bile duct areas and overgrowth of the liver were frequently observed, and these mice eventually developed HCC and cholangiocarcinoma (CCA) [43,46]. Of note, when YAP was additionally deleted in the NF2 knockout model, overgrowth of the liver and HCC incidence were reduced, indicating that hepatocarcinogenesis in the NF2 knockout models is mediated by activation of YAP.
In liver-specific MST1/2 knockout models, liver mass was generally increased due to elevated cell proliferation and ultimately HCC was induced. In the knockout models, proliferation and cell death were both increased, nevertheless, hepatomegaly is detected because the cell proliferation rate is much faster than the cell death rate [47,49]. In addition, nuclear accumulation of YAP increased in liver cells of the MST1/2 knockout mice via suppressing phosphorylation of YAP and Mob1 [19,48,51]. It should be noted that when either MST1 or MST2 was singly deleted, the liver size was not affected, suggesting that the MST1 and MST2 act in a redundant manner to control liver size [44,49,51]. In Mst1/2 knockout models, increases in the inflammatory reaction were also detected along with the upregulation of monocyte chemoattractant protein-1 (Mcp1), an inflammatory cytokine [50,62]. Genetic ablation of Mcp1 together with MST1/2 led to a reduction in inflammation, and ultimately to reduced tumor growth. In addition, when heterozygous deletion of YAP was induced in liver-specific MST1/2 knockout models, Mcp1 expression was inhibited and liver sizes returned to normal [50]. This strongly suggests that the inhibition of Hippo signaling induces liver inflammation via YAP-mediated transcriptional activation of Mcp1. Overall, MST1/2 determines the size of the liver by regulating the activity of YAP, and the suppression of MST1/2 can induce pro-tumorigenic inflammation in the liver and eventually HCC. Sav1 knockout models also showed hepatomegaly and the development of liver cancer, as seen in knockouts of other components of the Hippo signaling pathway [49,52]. In addition, double knockouts of Sav1 and PTEN dramatically accelerated tumorigenesis in the liver, compared with a single knockout of Sav1 [53].
Knockouts of Lats1/2 are mainly related to excessive biliary cell proliferation and carcinogenesis in the liver [55]. When the elevated YAP/TAZ activity was reduced by heterozygous deletion of YAP, hepatomegaly and hyperproliferation of bile duct cells were abolished [54,56]. These results show that Lats1/2 can control the liver size and biliary cell proliferation by acting as a negative upstream regulator of YAP. The dual deletion of Mob1A and Mob1B phenocopied characteristics of NF2 or Mst1/2 knockout models such as hepatomegaly, increased proliferation of bile duct cells, and incidences of HCC and CCA [57].
When YAP/TAZ was overexpressed in the liver via a transgenic approach, cellular proliferation was activated in the organ leading to increased liver volume without a visible tumor, whereas the knockout of YAP or TAZ led to decreased cell proliferation [63,64,65,66]. Recently, a simple liver-specific transgenic method has been developed via hydrodynamic tail vein injection (HTVI) [67,68,69,70,71]. The HTVI transgenesis allows an oncogene or oncogenic combinations to be expressed in hepatocytes. The expression of YAP or TAZ alone in the adult livers using the HTVI methodology did not lead to the development of tumors in the liver, but induced hyperproliferation and dedifferentiation of hepatocytes, suggesting requirements of other oncogenic partners for hepatocarcinogenesis in adults [67,72]. The co-expression of RAS together with TAZ led to the development of HCC at about 6 weeks after HTVI, while the expression of YAP plus PI3KCA induced CC-like tumors [60,61].

2.4. Preclinical Studies Targeting YAP/TAZ Signaling in HCC

Small molecules targeting YAP/TAZ signaling are currently limited. Verteporfin (VP) is a small molecule inhibitor of YAP/TAZ that disrupts the interaction between YAP/TAZ and TEADs, suppressing transcriptional activities of YAP/TAZ [73,74]. It is also known to increase the level of cytosolic YAP/TAZ [75]. VP suppressed tumor cell proliferation in HCC as well as other types of cancers such as retinoblastoma [73], and colon cancer [76,77]. VP showed enhancement in anti-cancer effects when used in combination with other drugs. Sorafenib (SF) is a multi-kinase inhibitor that is currently widely used for patients with HCC. Although SF alone showed minimal anti-cancer effects, treatment with VP and SF together exerted a synergistic effect on tumor cell death. Xenograft HCC models also showed similar results [78]. Using a subcutaneous xenograft tumor model, the combination of VP and other anti-cancer drugs such as 5-FU or Doxorubicin led to significantly reduced tumor growth by elevating apoptosis rates of tumor cells [79].
Vestigial Like Family Member 4 (VGLL4) is a tumor suppressor that competes with YAP in binding to TEADs, and thus, inhibits the transcriptional activity of YAP [16,76]. Finding that domains in the carboxyl-terminal of VGLL4 (TDU domain) are sufficient for the interaction with TEADs, short peptides mimicking the TDU domain have been developed, among which Super TDU is noteworthy [27,80,81]. In gastric cancer, treatment with Super-TDU effectively suppressed the proliferation of cancer cells. Further, Super-TDU suppressed HCC in subcutaneous and intrahepatic xenograft models via the inhibition of YAP/TAZ activities [82].
Sitagliptin is an oral hypoglycemic agent that is widely used in many countries to treat diabetes [83]. Its mechanism of action is through the inhibition of dipeptidyl peptidase-4 (DPP-4), an enzyme that degrades and inactivates glucagon-like peptide-1 (GLP-1). The elevated GLP-1 level in response to sitagliptin leads to increased insulin release and improves glucose tolerance. Recently, it was found that sitagliptin inhibited YAP nuclear translocation [83]. The inhibitory effect on YAP exerted by sitagliptin is mediated via its activation of AMP-activated protein kinase (AMPK), which does not only promote phosphorylation of LATS1/2 but also directly phosphorylates YAP, leading to cytoplasmic retention and degradation of the transcription factor [83]. Besides sitagliptin, other AMPK agonists such as metformin and phenformin can also exert similar inhibitory effects on YAP. In chemically induced HCC mouse models, the treatment of tumor-bearing mice with sitagliptin at a dose of 80 mg/kg for 60 days significantly prolonged the survival of the treated mice and reduced malignancies of HCC in the animals [84].

3. Targeting Hedgehog Signaling in Liver Cancer

3.1. Hedgehog Signaling Pathway

The Hedgehog genes were first identified in the late 1970s through the genetic screening of mutations leasing to “spiked” phenotypes of the cuticle of Drosophila [85,86,87,88]. It has been later found that the genes are highly conserved from Drosophila to mammals. Hedgehog signaling regulates cell proliferation, differentiation, tissue homeostasis, and carcinogenesis [85,87,89,90,91]. In humans, there are three types of Hedgehog ligands: Sonic Hedgehog (Shh), Indian Hedgehog (Ihh) and Desert Hedgehog (Dhh) [86,87].
The canonical Hedgehog signaling pathway is activated when Hedgehog ligands bind to the receptors, Patched (Ptch) proteins (Figure 2) [87]. In the absence of Hedgehog ligands, Ptch continues to repress the activity of Smoothened (Smo), a G-protein-coupled receptor-like protein and inhibits translocation of Smo to the primary cilium (PC) [86,87,89,90,92,93]. When Smo is not located in PC, a Glioma-associated oncogene (Gli) is phosphorylated by protein kinase A (PKA), glycogen synthase kinase-3 (GSK3), and casein kinase 1 (CK1) [89,90,94,95,96,97]. Phosphorylated Gli undergoes proteolytic cleavage by β-transducin-repeat-containing protein (β-TrCP), generating Gli repressor (GliR) [89,94,95,96,98]. GliR binds to the promoters of Hedgehog target genes, suppressing their transcription. In contrast, the binding of Hedgehog ligands to Ptch relieves the suppression of Smo by the receptor protein, leading to the translocation of Smo to PC [87,92,99]. The presence of Smo in PC suppresses phosphorylation and proteolytic cleavage of Gli. It is also suggested that Smo activates Gli by relieving inhibition of Gli by kinesin protein (Kif7) and Suppressor of fused (Sufu) [89,95,98]. The release of Gli from the inhibitory protein complex allows Gli to be active (GliA) and to translocate into the nucleus where it activates the transcription of a plethora of Hedgehog target genes [87,89]. In addition to the canonical Hedgehog pathway, there are two types of non-canonical Hedgehog pathways that do not involve Gli-mediated transcription regulation of hedgehog target genes [94,100]. Type I non-canonical pathway is Smo-independent, while Type II is Smo-dependent. Non-canonical Hedgehog signaling pathways are beyond the scope of this review and detailed information can be found elsewhere [94,99,100,101,102].

3.2. Hedgehog Signaling in Liver Cancer

The synthesis of hedgehog ligands is stimulated by diverse factors that trigger liver regeneration, which include various liver mitogens and cell stressors. The Hedgehog ligands are released from ligand-producing cells into the local environment where they engage receptors on Hedgehog responsive cells. In particular, Sonic Hedgehog (Shh), the representative Hedgehog ligand, enhances the viabilities of Hedgehog target cells, serving as viability and proliferative factors for various types of liver cells [89,94]. Shh is overexpressed in approximately 60% of human HCC, suggesting that Hedgehog pathway activation contributes to hepatocarcinogenesis [103,104,105,106].
Shh is strongly expressed in the ventral foregut endoderm where liver, pancreas and lung buds develop [94]. Shh is also expressed temporarily in hepatoblasts later in development [94]. As hepatoblasts differentiate into hepatocytes, the expression of Shh decreases [94]. Therefore, the Shh pathway is activated in liver embryogenesis, but it is mostly inactive in mature hepatocytes in healthy adult liver [107]. The Shh pathway can be re-activated in adult livers when acute or chronic liver regeneration is induced. Various liver cells such as hepatocytes, cholangiocytes, myofibroblastic stellate cells, sinusoidal endothelial cells, and immune cells produce Shh for wound healing in an injured liver [89,94].
The elevated expression of Shh and its target genes such as Ptch and Gli was detected in HCC tissues [104,107,108,109]. It is also demonstrated that the Shh signaling pathway elicits cell migration and invasion of HCC cells. Down-regulation of Gli using siRNA inhibited adhesion, migration and invasion of HCC [110]. Further, treatment with Shh enhanced migration and invasion of HCC cells such as LO2, SMMC-7721, and SK-Hep [111,112].

3.3. Animal Models of Liver Cancer Induced by Activated Hedgehog Signaling

Various studies employing animal models have demonstrated that the Hedgehog signaling pathway plays an important role in hepatocarcinogenesis. A transgenic mouse model was developed in which Shh is secreted from hepatocytes, which mimics histopathological features of patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) [113]. Secreted Shh in the model activated Hedgehog signaling in numerous cells of various types in the hepatic tissue and led to hepatic fibrosis and hepatocarcinogenesis [114]. Moreover, the Mdr2 knockout model consistently expressed Hedgehog ligands and progressively accumulated myofibroblasts and progenitors in the liver with age [105]. Activated Hedgehog signaling in the model led to chronic inflammation, liver injury and fibrosis, and finally HCC [105]. Of note, the treatment of Mdr2-deficient mice with an inhibitor of Hedgehog signaling suppressed liver fibrosis and HCC [105].
Genetic ablation of Smo in myofibroblasts can be achieved using SMOflox/flox; αSMA-CreERT2 mice in which treatment with tamoxifen induces nuclear import of Cre recombinases in myofibroblasts and leaves out an exon of Smo gene [115]. The treatment of SMOflox/flox; αSMA-CreERT2 mice with tamoxifen showed a blockade of Hedgehog signaling selectively in myofibroblasts and inhibited liver fibrosis [115]. This suggests that the activation of Hedgehog signaling in myofibroblasts is critical in inducing liver fibrosis. Considering the strong correlation between hepatic fibrosis and liver cancer, the data suggest that Hedgehog activation in hepatic stroma promotes liver cancer.

3.4. Preclinical Studies Targeting Hedgehog Signaling in HCC

Preclinical studies targeting the Hedgehog signaling pathway mainly focus on the inhibition of the activity of Smo. For example, cyclopamine can block the Hedgehog signaling pathway by inhibiting Smo. It is demonstrated that cyclopamine increased apoptosis and decreased cells growth and proliferation in various HCC cell lines including SMMC-7721, SK-Hep1, Hep3B, Huh7, and PLC [103,104,108,116]. Vismodegib is also a potent inhibitor of Smo. In in vivo preclinical studies, both cyclopamine and vismodegib inhibited the growth of tumors in the liver [117]. Hepatitis B virus X protein-expressing transgenic mice (HBxTg) develop hepatitis and steatosis by 5 to 6 months of age, dysplastic nodules by 8 to 9 months, and visible HCC by 12 months [118]. Of note, the HBxTg mice exhibited increased levels of Gli2 and Shh in the livers. Treatment of the HBxTg mice with vismodegib downregulated the levels of Gli2 and Shh and more importantly, suppressed tumor development in their livers [118].
Taccalonolide A is a Hedgehog antagonist. Treatment with Taccalonolide A decreased mRNA levels of Hedgehog signaling molecules and led to reduced viability of HCC cells [119]. GANT61 is a selective inhibitor of Gli-mediated transactivation [120,121]. Preclinical studies were performed for numerous cancer types, including rhabdomyosarcoma, neuroblastoma, and leukemia, as well as colon and pancreatic cancer. In HCC, treatment with GANT61 significantly reduced cell proliferation and viability [120]. In an HCC xenograft model transplanted with Huh7 cells, the administration of GANT61 inhibited tumor formation and growth [120].

4. Targeting Wnt/β-Catenin Signaling in Liver Cancer

4.1. Wnt/β-Catenin Signaling Pathway

The Wnt/β-catenin signaling is a signal transduction pathway that initiates with the binding of Wnt protein to its receptor Frizzled and then transmits the signal through β-catenin. In the absence of Wnt, β-catenin is downregulated by a destruction complex which consists of Glycogenesis kinase3β (GSK3β) and casein kinase1α (CK1α), tumor suppressor adenomatous polyposis coli (APC), and scaffold protein AXIN (Figure 3) [122,123]. The β-catenin destruction complex phosphorylates the N-terminus of β-catenin through GSK3β and CK1α [124,125]. Phosphorylated β-catenin is ubiquitinated by β-transducin-repeat-containing protein (β-TrCP) ubiquitin ligase and destroyed by the proteasome [124,126]. Endogenous Wnt antagonists such as secreted frozen-related proteins (SFRPs), Dickkopfs (DKKs), and Wnt Inhibitory factors (WIFs) suppress Wnt/ β-catenin signaling by inhibiting the interaction between Wnt ligands and the receptors, Frizzled [124,127,128,129,130].
The binding of Wnt to receptors Frizzled on the cell surface recruits phosphoprotein Dishevelled (Dvl) to the receptor, providing a binding site for Axin and GSK3β. This event leads to phosphorylation of transmembrane low-density lipoprotein receptor-related protein5/6 (LRP5/6), and more importantly inhibits phosphorylation of β-catenin by GSK3β [6,131]. Unphosphorylated β-catenin can escape from ubiquitin-mediated protein degradation, and thus, increases its concentration in the cytoplasm [6,131]. Accumulated β-catenin can translocate into the nucleus, where it interacts with the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) for transcriptional activation of numerous target genes [122,132]. Genes related to cell proliferation (MYC, MYB, CYD1, etc.), angiogenesis (VEGF and c-MET), and anti-apoptosis (Bcl-2 and Survivin) are some of the target genes of Wnt/β-catenin signaling [6,133,134,135]. There are other transcription factors such as hypoxia-inducible factor 1α (HIFIα), forkhead box protein O (FOXO), and several members of the sex-determining region Y box (SOX) family with which β-catenin associates for transcriptional activation [136,137,138,139,140].

4.2. Wnt/β-Catenin Signaling in Liver Cancer

Studies have shown that there is a strong correlation between the level of nuclear β-catenin and the tumor grade of HCC [141,142]. Elevated levels of nuclear β-catenin in HCC have also been associated with increased proliferation of tumor cells in HCC [143,144]. Aberrant activation of the Wnt/β-catenin signaling pathway or deregulated nuclear accumulation of β-catenin can be caused by mutations in components of the pathways, which are frequently found in HCC [136,137]. Accumulation of β-catenin plays important role in HCC development. About 20–35% of HCCs are caused by genetic mutations in the CTNNB1 gene (coding for β-catenin), rendering the protein resistant to degradation [136,145]. Three-fourths of CTNNB1 mutations are caused by missense substitution which occurs at exon 3 at amino acid position 29–49 [136,146,147]. The exon 3 of β-catenin has multiple target sites for phosphorylation by GSK3 as well as ubiquitination sites for degradation by the proteasome [148,149]. Thus, mutation at these phosphorylation and ubiquitination sites can enhance the stability of β-catenin.
The fact that the accumulation of β-catenin in HCC is more frequently found than mutations in CTNNB1 strongly suggests that loss-of-function mutation in negative regulators of β-catenin such as APC or AXIN should be present in HCC. In line with the speculation, a loss-of-function mutation in AXIN occurs at a frequency of 3–16% in HCC, which is the second most common mutation in HCC that leads to activation of the Wnt/β-catenin signaling pathway [124,146,150]. The AXIN mutation suppresses the degradation of β-catenin by inhibiting its phosphorylation [124,151,152]. Satoh et al. reported that they found 13 genetic alterations in CTNNB1 among 100 primary HCC tissues. Of note, they found 6 mutations in AXIN1 in the 87 tumor samples that had no CTNNB1 mutations, underlining the significance of AXIN1 mutation in human HCC [124,151,152]. Unlike mutations in CTNNB1, 37.5% of mutations found in AXIN are nonsense mutations, while only 30% of mutations are attributed to missense mutations [133,136].

4.3. Animal Models of Liver Cancer Induced by Activated Wnt/β-Catenin Signaling

Although aberrant activation of β-catenin is frequently found in human HCC, the expression of a constitutively active form of β-catenin alone was not enough to develop HCC in murine models [153,154]. This strongly suggests that the Wnt/β-catenin signaling pathway requires an oncogenic collaborator for the development of HCC [155,156,157]. Genetically engineered mouse models have revealed that activated Wnt/β-catenin signaling can effectively cooperate with activated RAS, MET, and AKT signaling pathways to induce HCC (Table 2). For example, the expression of a constitutively active form of NRAS (NRASG12V) alone did not induce HCC, while the co-expression of NRASG12V with an activated mutant form of β-catenin led to the formation of HCC [157]. The simultaneous expression of c-Met and active β-catenin also developed HCC at 12 weeks following the expression [158]. Considering that one-fifth of human HCC showed overexpression/activation of both c-Met and β-catenin, the double transgenic mouse models well represent human HCC of this subset [158,159].
The co-activation of both the Wnt/β-catenin and Akt/mTOR pathways is found in about 10% of patients with HCC who frequently show poor survival. Toh et al. reported that the co-expression of constitutively active forms of human AKT and β-catenin led to the formation of a high HCC tumor burden in both male and female FVB/N mice with 100% penetrance [160]. Of note, tumors induced by the co-activation of AKT and Wnt/ β-catenin signaling pathways contained a subpopulation of cells with stem/progenitor-like characteristics, which may contribute to tumor self-renewal and drug resistance [160].

4.4. Preclinical Studies Targeting Wnt/β-Catenin Signaling in HCC

Based on the frequent activation of Wnt/β-catenin signaling in HCC, various molecules targeting the signaling pathway have been tested for HCC treatment. In an attempt to block the initiation step of the signaling cascade, monoclonal antibodies such as OMP-18R5 have been developed which bind to Frizzled receptors and inhibit its interaction with Wnt ligands. OMP-18R5 showed suppression of tumors in xenograft models of various types of cancers [161]. OMP-54F28 is a fusion protein combining the frizzled family receptor 8 (FZD8) with the immunoglobulin Fc domain which is designed to compete with the native Frizzled receptors for Wnt ligands. OMP-54F28 suppressed Wnt activation and reduced tumor growth in patient-derived xenograft models [162,163].
Considering that Frizzled receptor 7 (FZD7) is most frequently overexpressed in HCC among the 10 human Frizzled receptors [164], small interfering peptides were developed that disrupt the interaction of FZD7 with Dvl (Figure 3). The treatment of HCC cells with the peptides containing the Dvl-binding motif of FZD7 decreased the cell viability of the tumor cells through β-catenin degradation [165]. Fz7-21 is another peptide antagonist of Frizzled receptor 7 which is isolated from a peptide phage library [166]. The peptide specifically binds to FZD7 and impairs the interaction of FZD7 with Wnt ligands. Two human hepatoma cell lines, HepG2 and Huh-7 with high expression levels of FZD7 were selected to test the efficacy of Fz7-21 as an antagonist of Wnt/β-catenin signaling. Treatment with Fz7-21 strongly inhibited the Wnt/β-catenin signaling pathway in the cell lines and subsequently induced apoptosis and anti-proliferative effects on HCC cells [167].
CGP049090, PKF118-310, and PKF115-584 are small molecules that inhibit the interaction between Tcf4 and β-catenin, and thus suppress the transcriptional activity of the Tcf4/β-catenin complex. In in vitro studies, treatment with the inhibitors induced apoptosis and cell cycle arrest in human hepatoma cell lines, HepG2, Hep40, and Huh-7 [168,169]. Further, in athymic nude mice transplanted with HepG2 cells, treatment with each of the chemicals significantly suppressed the growths of tumors in the xenograft models. Molecular analysis of harvested tumor tissues revealed substantially increased apoptosis in tumors treated with the inhibitors. Further, tumors treated with the inhibitors showed reduced expression levels of c-Myc, cyclin D1 and survivin, which are transcriptional targets of TCF4/β-catenin [168,170].
Tankyrase acts as an activator of Wnt/β-catenin signaling by mediating the degradation of AXIN1 and AXIN2 which are negative regulators of β-catenin [170]. NVP-TNKS656 inhibits tankyrase by binding to the dual active pockets in tankyrase [171]. In HCC cell lines such as SMMC-7721 and MHHC97H, NVP-TNKS656 blocked cell proliferation and clone formation [172]. Further, the drug also suppressed migration and invasion of HCC cells [171,172,173]. Anther tankyrase inhibitor, XAV939, also inhibited cell proliferation and colony formation in HCC cell lines (Table 3). In xenograft models transplanted with HepG2, intra-tumor injections of XAV939 significantly suppressed tumor growth [174].

5. Perspectives and Conclusions

The development of HCC is a complex, multi-step process accompanied by alterations in multiple signaling cascades. A fundamental understanding of molecular signaling pathways to tumorigenesis can help predict patient response to targeted therapies, which can have a substantial impact on clinical decision-making. Of all the tumor driver genes, those responsible for oncogenic addiction are important [175,176]. Accumulating data have shown that YAP/TAZ, Hedgehog, and Wnt/β-catenin signaling pathways play central roles in carcinogenesis of HCC and could be the promising Achilles’ heel to attack cancer.
Most studies targeting the YAP/TAZ, Hedgehog, or Wnt/β-catenin signaling pathways in HCC are currently under preclinical stages in which the target therapies have reduced cell viability, proliferation and migratory potentials of HCC. Phase I and/or II clinical trials targeting the signaling pathways have been completed or are undergoing (Table 4). With the advancement in drug discovery and screening, safe and effective target therapeutics will be developed and tested for HCC in clinical settings. For instance, BC2059 and DKN-01 are drugs targeting the Wnt//β-catenin signaling pathway, and they have shown tumor suppression in murine models of acute myeloid leukemia and ovarian cancer, respectively [177,178]. The target therapeutics wait for phase I/II clinical trials for patients with HCC. We look forward to seeing how effective the novel target therapies will be in HCC in clinical trials.

Author Contributions

All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant (2019R1A2C2009518 awarded to SWR) which was funded by the Korean government (MSIT).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Llovet, J.M.; Kelley, R.K.; Villanueva, A.; Singal, A.G.; Pikarsky, E.; Roayaie, S.; Lencioni, R.; Koike, K.; Zucman-Rossi, J.; Finn, R.S. Hepatocellular carcinoma. Nat. Rev. Dis. Primers 2021, 7, 6. [Google Scholar] [CrossRef] [PubMed]
  2. Singal, A.G.; Lampertico, P.; Nahon, P. Epidemiology and surveillance for hepatocellular carcinoma: New trends. J. Hepatol. 2020, 72, 250–261. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Banales, J.M.; Marin, J.J.G.; Lamarca, A.; Rodrigues, P.M.; Khan, S.A.; Roberts, L.R.; Cardinale, V.; Carpino, G.; Andersen, J.B.; Braconi, C.; et al. Cholangiocarcinoma 2020: The next horizon in mechanisms and management. Nat. Rev. Gastroenterol. Hepatol. 2020, 17, 557–588. [Google Scholar] [CrossRef] [PubMed]
  4. Villanueva, A. Hepatocellular Carcinoma. N. Engl. J. Med. 2019, 380, 1450–1462. [Google Scholar] [CrossRef] [Green Version]
  5. Llovet, J.M.; Montal, R.; Sia, D.; Finn, R.S. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 2018, 15, 599–616. [Google Scholar] [CrossRef]
  6. Dimri, M.; Satyanarayana, A. Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma. Cancers 2020, 12, 491. [Google Scholar] [CrossRef] [Green Version]
  7. Moon, H.; Ro, S.W. MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma. Cancers 2021, 13, 3026. [Google Scholar] [CrossRef]
  8. Huang, A.; Yang, X.R.; Chung, W.Y.; Dennison, A.R.; Zhou, J. Targeted therapy for hepatocellular carcinoma. Signal. Transduct. Target. Ther. 2020, 5, 146. [Google Scholar] [CrossRef]
  9. Rizvi, S.; Wang, J.; El-Khoueiry, A.B. Liver Cancer Immunity. Hepatology 2021, 73 (Suppl. S1), 86–103. [Google Scholar] [CrossRef]
  10. Pinato, D.J.; Guerra, N.; Fessas, P.; Murphy, R.; Mineo, T.; Mauri, F.A.; Mukherjee, S.K.; Thursz, M.; Wong, C.N.; Sharma, R.; et al. Immune-based therapies for hepatocellular carcinoma. Oncogene 2020, 39, 3620–3637. [Google Scholar] [CrossRef] [Green Version]
  11. Greten, T.F.; Lai, C.W.; Li, G.; Staveley-O’Carroll, K.F. Targeted and Immune-Based Therapies for Hepatocellular Carcinoma. Gastroenterology 2019, 156, 510–524. [Google Scholar] [CrossRef] [PubMed]
  12. Sangro, B.; Sarobe, P.; Hervás-Stubbs, S.; Melero, I. Advances in immunotherapy for hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 2021, 18, 525–543. [Google Scholar] [CrossRef] [PubMed]
  13. Llovet, J.M.; Castet, F.; Heikenwalder, M.; Maini, M.K.; Mazzaferro, V.; Pinato, D.J.; Pikarsky, E.; Zhu, A.X.; Finn, R.S. Immunotherapies for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 2021, 19, 151–172. [Google Scholar] [CrossRef] [PubMed]
  14. Chang, Y.C.; Wu, J.W.; Wang, C.W.; Jang, A.C. Hippo Signaling-Mediated Mechanotransduction in Cell Movement and Cancer Metastasis. Front. Mol. Biosci. 2019, 6, 157. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Misra, J.R.; Irvine, K.D. The Hippo Signaling Network and Its Biological Functions. Annu. Rev. Genet. 2018, 52, 65–87. [Google Scholar] [CrossRef] [PubMed]
  16. Park, J.H.; Shin, J.E.; Park, H.W. The Role of Hippo Pathway in Cancer Stem Cell Biology. Mol. Cells 2018, 41, 83–92. [Google Scholar] [CrossRef] [PubMed]
  17. Rausch, V.; Hansen, C.G. The Hippo Pathway, YAP/TAZ, and the Plasma Membrane. Trends Cell Biol. 2020, 30, 32–48. [Google Scholar] [CrossRef]
  18. Karaman, R.; Halder, G. Cell Junctions in Hippo Signaling. Cold Spring Harb. Perspect Biol. 2018, 10, a028753. [Google Scholar] [CrossRef]
  19. Liu, A.M.; Xu, Z.; Luk, J.M. An update on targeting Hippo-YAP signaling in liver cancer. Expert Opin. Ther. Targets 2012, 16, 243–247. [Google Scholar] [CrossRef]
  20. Yu, F.X.; Zhao, B.; Guan, K.L. Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. Cell 2015, 163, 811–828. [Google Scholar] [CrossRef] [Green Version]
  21. Ma, Y.; Yang, Y.; Wang, F.; Wei, Q.; Qin, H. Hippo-YAP signaling pathway: A new paradigm for cancer therapy. Int. J. Cancer 2015, 137, 2275–2286. [Google Scholar] [CrossRef] [PubMed]
  22. Hansen, C.G.; Moroishi, T.; Guan, K.L. YAP and TAZ: A nexus for Hippo signaling and beyond. Trends Cell Biol. 2015, 25, 499–513. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Boopathy, G.T.K.; Hong, W. Role of Hippo Pathway-YAP/TAZ Signaling in Angiogenesis. Front. Cell Dev. Biol. 2019, 7, 49. [Google Scholar] [CrossRef] [PubMed]
  24. Moon, H.; Cho, K.; Shin, S.; Kim, D.Y.; Han, K.H.; Ro, S.W. High Risk of Hepatocellular Carcinoma Development in Fibrotic Liver: Role of the Hippo-YAP/TAZ Signaling Pathway. Int. J. Mol. Sci. 2019, 20, 581. [Google Scholar] [CrossRef] [Green Version]
  25. Pan, D. The hippo signaling pathway in development and cancer. Dev. Cell 2010, 19, 491–505. [Google Scholar] [CrossRef] [Green Version]
  26. Liu, Y.; Wang, X.; Yang, Y. Hepatic Hippo signaling inhibits development of hepatocellular carcinoma. Clin. Mol. Hepatol. 2020, 26, 742–750. [Google Scholar] [CrossRef]
  27. Ortega, Á.; Vera, I.; Diaz, M.P.; Navarro, C.; Rojas, M.; Torres, W.; Parra, H.; Salazar, J.; Sanctis, J.B.; Bermúdez, V. The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises. Int. J. Mol. Sci. 2021, 23, 430. [Google Scholar] [CrossRef]
  28. Zanconato, F.; Cordenonsi, M.; Piccolo, S. YAP/TAZ at the Roots of Cancer. Cancer Cell 2016, 29, 783–803. [Google Scholar] [CrossRef] [Green Version]
  29. Yang, D.; Zhang, N.; Li, M.; Hong, T.; Meng, W.; Ouyang, T. The Hippo Signaling Pathway: The Trader of Tumor Microenvironment. Front. Oncol. 2021, 11, 772134. [Google Scholar] [CrossRef]
  30. Xu, M.Z.; Yao, T.J.; Lee, N.P.; Ng, I.O.; Chan, Y.T.; Zender, L.; Lowe, S.W.; Poon, R.T.; Luk, J.M. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer 2009, 115, 4576–4585. [Google Scholar] [CrossRef] [Green Version]
  31. LaQuaglia, M.J.; Grijalva, J.L.; Mueller, K.A.; Perez-Atayde, A.R.; Kim, H.B.; Sadri-Vakili, G.; Vakili, K. YAP Subcellular Localization and Hippo Pathway Transcriptome Analysis in Pediatric Hepatocellular Carcinoma. Sci. Rep. 2016, 6, 30238. [Google Scholar] [CrossRef] [PubMed]
  32. Shan, L.; Jiang, H.; Ma, L.; Yu, Y. Yes-associated protein: A novel molecular target for the diagnosis, treatment and prognosis of hepatocellular carcinoma. Oncol. Lett. 2017, 14, 3291–3296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Han, S.X.; Bai, E.; Jin, G.H.; He, C.C.; Guo, X.J.; Wang, L.J.; Li, M.; Ying, X.; Zhu, Q. Expression and clinical significance of YAP, TAZ, and AREG in hepatocellular carcinoma. J. Immunol. Res. 2014, 2014, 261365. [Google Scholar] [CrossRef] [PubMed]
  34. Wang, H.; Wang, J.; Zhang, S.; Jia, J.; Liu, X.; Zhang, J.; Wang, P.; Song, X.; Che, L.; Liu, K.; et al. Distinct and Overlapping Roles of Hippo Effectors YAP and TAZ During Human and Mouse Hepatocarcinogenesis. Cell. Mol. Gastroenterol. Hepatol. 2021, 11, 1095–1117. [Google Scholar] [CrossRef] [PubMed]
  35. Xiao, H.; Jiang, N.; Zhou, B.; Liu, Q.; Du, C. TAZ regulates cell proliferation and epithelial-mesenchymal transition of human hepatocellular carcinoma. Cancer Sci. 2015, 106, 151–159. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Guo, Y.; Pan, Q.; Zhang, J.; Xu, X.; Liu, X.; Wang, Q.; Yi, R.; Xie, X.; Yao, L.; Liu, W.; et al. Functional and clinical evidence that TAZ is a candidate oncogene in hepatocellular carcinoma. J. Cell. Biochem. 2015, 116, 2465–2475. [Google Scholar] [CrossRef]
  37. Shi, C.; Cai, Y.; Li, Y.; Li, Y.; Hu, N.; Ma, S.; Hu, S.; Zhu, P.; Wang, W.; Zhou, H. Yap promotes hepatocellular carcinoma metastasis and mobilization via governing cofilin/F-actin/lamellipodium axis by regulation of JNK/Bnip3/SERCA/CaMKII pathways. Redox Biol. 2018, 14, 59–71. [Google Scholar] [CrossRef] [PubMed]
  38. Wang, X.; Wu, B.; Zhong, Z. Downregulation of YAP inhibits proliferation, invasion and increases cisplatin sensitivity in human hepatocellular carcinoma cells. Oncol. Lett. 2018, 16, 585–593. [Google Scholar] [CrossRef]
  39. Zhang, S.; Zhou, D. Role of the transcriptional coactivators YAP/TAZ in liver cancer. Curr. Opin. Cell Biol. 2019, 61, 64–71. [Google Scholar] [CrossRef]
  40. Hagenbeek, T.J.; Webster, J.D.; Kljavin, N.M.; Chang, M.T.; Pham, T.; Lee, H.J.; Klijn, C.; Cai, A.G.; Totpal, K.; Ravishankar, B.; et al. The Hippo pathway effector TAZ induces TEAD-dependent liver inflammation and tumors. Sci. Signal. 2018, 11, 1757. [Google Scholar] [CrossRef]
  41. Thompson, B.J. YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy. BioEssays 2020, 42, e1900162. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Yimlamai, D.; Fowl, B.H.; Camargo, F.D. Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer. J. Hepatol. 2015, 63, 1491–1501. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Zhang, N.; Bai, H.; David, K.K.; Dong, J.; Zheng, Y.; Cai, J.; Giovannini, M.; Liu, P.; Anders, R.A.; Pan, D. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 2010, 19, 27–38. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Valero, V., 3rd; Pawlik, T.M.; Anders, R.A. Emerging role of Hpo signaling and YAP in hepatocellular carcinoma. J. Hepatocell Carcinoma 2015, 2, 69–78. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Yimlamai, D.; Christodoulou, C.; Galli, G.G.; Yanger, K.; Pepe-Mooney, B.; Gurung, B.; Shrestha, K.; Cahan, P.; Stanger, B.Z.; Camargo, F.D. Hippo pathway activity influences liver cell fate. Cell 2014, 157, 1324–1338. [Google Scholar] [CrossRef] [Green Version]
  46. Benhamouche, S.; Curto, M.; Saotome, I.; Gladden, A.B.; Liu, C.H.; Giovannini, M.; McClatchey, A.I. Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes Dev. 2010, 24, 1718–1730. [Google Scholar] [CrossRef] [Green Version]
  47. Song, H.; Mak, K.K.; Topol, L.; Yun, K.; Hu, J.; Garrett, L.; Chen, Y.; Park, O.; Chang, J.; Simpson, R.M.; et al. Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc. Natl. Acad. Sci. USA 2010, 107, 1431–1436. [Google Scholar] [CrossRef] [Green Version]
  48. Fitamant, J.; Kottakis, F.; Benhamouche, S.; Tian, H.S.; Chuvin, N.; Parachoniak, C.A.; Nagle, J.M.; Perera, R.M.; Lapouge, M.; Deshpande, V.; et al. YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression. Cell Rep. 2015, 10, 1692–1707. [Google Scholar] [CrossRef] [Green Version]
  49. Lu, L.; Li, Y.; Kim, S.M.; Bossuyt, W.; Liu, P.; Qiu, Q.; Wang, Y.; Halder, G.; Finegold, M.J.; Lee, J.S.; et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc. Natl. Acad. Sci. USA 2010, 107, 1437–1442. [Google Scholar] [CrossRef] [Green Version]
  50. Kim, W.; Khan, S.K.; Liu, Y.; Xu, R.; Park, O.; He, Y.; Cha, B.; Gao, B.; Yang, Y. Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. Gut 2018, 67, 1692–1703. [Google Scholar] [CrossRef]
  51. Zhou, D.; Conrad, C.; Xia, F.; Park, J.S.; Payer, B.; Yin, Y.; Lauwers, G.Y.; Thasler, W.; Lee, J.T.; Avruch, J.; et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 2009, 16, 425–438. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Lee, K.P.; Lee, J.H.; Kim, T.S.; Kim, T.H.; Park, H.D.; Byun, J.S.; Kim, M.C.; Jeong, W.I.; Calvisi, D.F.; Kim, J.M.; et al. The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. Proc. Natl. Acad. Sci. USA 2010, 107, 8248–8253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Jeong, S.H.; Kim, H.B.; Kim, M.C.; Lee, J.M.; Lee, J.H.; Kim, J.H.; Kim, J.W.; Park, W.Y.; Kim, S.Y.; Kim, J.B.; et al. Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer. J. Clin. Investig. 2018, 128, 1010–1025. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Yi, J.; Lu, L.; Yanger, K.; Wang, W.; Sohn, B.H.; Stanger, B.Z.; Zhang, M.; Martin, J.F.; Ajani, J.A.; Chen, J.; et al. Large tumor suppressor homologs 1 and 2 regulate mouse liver progenitor cell proliferation and maturation through antagonism of the coactivators YAP and TAZ. Hepatology 2016, 64, 1757–1772. [Google Scholar] [CrossRef] [Green Version]
  55. Lee, D.H.; Park, J.O.; Kim, T.S.; Kim, S.K.; Kim, T.H.; Kim, M.C.; Park, G.S.; Kim, J.H.; Kuninaka, S.; Olson, E.N.; et al. LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development. Nat. Commun. 2016, 7, 11961. [Google Scholar] [CrossRef]
  56. Chen, Q.; Zhang, N.; Xie, R.; Wang, W.; Cai, J.; Choi, K.S.; David, K.K.; Huang, B.; Yabuta, N.; Nojima, H.; et al. Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP. Genes Dev. 2015, 29, 1285–1297. [Google Scholar] [CrossRef] [Green Version]
  57. Nishio, M.; Sugimachi, K.; Goto, H.; Wang, J.; Morikawa, T.; Miyachi, Y.; Takano, Y.; Hikasa, H.; Itoh, T.; Suzuki, S.O.; et al. Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice. Proc. Natl. Acad. Sci. USA 2016, 113, E71–E80. [Google Scholar] [CrossRef] [Green Version]
  58. Dong, J.; Feldmann, G.; Huang, J.; Wu, S.; Zhang, N.; Comerford, S.A.; Gayyed, M.F.; Anders, R.A.; Maitra, A.; Pan, D. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 2007, 130, 1120–1133. [Google Scholar] [CrossRef] [Green Version]
  59. Camargo, F.D.; Gokhale, S.; Johnnidis, J.B.; Fu, D.; Bell, G.W.; Jaenisch, R.; Brummelkamp, T.R. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr. Biol. 2007, 17, 2054–2060. [Google Scholar] [CrossRef] [Green Version]
  60. Cho, K.; Ro, S.W.; Lee, H.W.; Moon, H.; Han, S.; Kim, H.R.; Ahn, S.H.; Park, J.Y.; Kim, D.Y. YAP/TAZ Suppress Drug Penetration Into Hepatocellular Carcinoma Through Stromal Activation. Hepatology 2021, 74, 2605–2621. [Google Scholar] [CrossRef]
  61. Li, X.; Tao, J.; Cigliano, A.; Sini, M.; Calderaro, J.; Azoulay, D.; Wang, C.; Liu, Y.; Jiang, L.; Evert, K.; et al. Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver. Oncotarget 2015, 6, 10102–10115. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Matthaios, D.; Tolia, M.; Mauri, D.; Kamposioras, K.; Karamouzis, M. YAP/Hippo Pathway and Cancer Immunity: It Takes Two to Tango. Biomedicines 2021, 9, 1949. [Google Scholar] [CrossRef] [PubMed]
  63. Manmadhan, S.; Ehmer, U. Hippo Signaling in the Liver—A Long and Ever-Expanding Story. Front. Cell Dev. Biol. 2019, 7, 33. [Google Scholar] [CrossRef] [PubMed]
  64. Patel, S.H.; Camargo, F.D.; Yimlamai, D. Hippo Signaling in the Liver Regulates Organ Size, Cell Fate, and Carcinogenesis. Gastroenterology 2017, 152, 533–545. [Google Scholar] [CrossRef] [Green Version]
  65. Nguyen-Lefebvre, A.T.; Selzner, N.; Wrana, J.L.; Bhat, M. The hippo pathway: A master regulator of liver metabolism, regeneration, and disease. FASEB J. 2021, 35, e21570. [Google Scholar] [CrossRef]
  66. Zhao, B.; Li, L.; Lei, Q.; Guan, K.L. The Hippo-YAP pathway in organ size control and tumorigenesis: An updated version. Genes Dev. 2010, 24, 862–874. [Google Scholar] [CrossRef] [Green Version]
  67. Chen, X.; Calvisi, D.F. Hydrodynamic transfection for generation of novel mouse models for liver cancer research. Am. J. Pathol. 2014, 184, 912–923. [Google Scholar] [CrossRef] [Green Version]
  68. Ju, H.L.; Han, K.H.; Lee, J.D.; Ro, S.W. Transgenic mouse models generated by hydrodynamic transfection for genetic studies of liver cancer and preclinical testing of anti-cancer therapy. Int. J. Cancer 2016, 138, 1601–1608. [Google Scholar] [CrossRef] [Green Version]
  69. Moon, H.; Ju, H.L.; Chung, S.I.; Cho, K.J.; Eun, J.W.; Nam, S.W.; Han, K.H.; Calvisi, D.F.; Ro, S.W. Transforming Growth Factor-β Promotes Liver Tumorigenesis in Mice via Up-regulation of Snail. Gastroenterology 2017, 153, 1378–1391.e1376. [Google Scholar] [CrossRef] [Green Version]
  70. Liu, Y.T.; Tseng, T.C.; Soong, R.S.; Peng, C.Y.; Cheng, Y.H.; Huang, S.F.; Chuang, T.H.; Kao, J.H.; Huang, L.R. A novel spontaneous hepatocellular carcinoma mouse model for studying T-cell exhaustion in the tumor microenvironment. J. Immunother. Cancer 2018, 6, 144. [Google Scholar] [CrossRef]
  71. Ruiz de Galarreta, M.; Bresnahan, E.; Molina-Sánchez, P.; Lindblad, K.E.; Maier, B.; Sia, D.; Puigvehi, M.; Miguela, V.; Casanova-Acebes, M.; Dhainaut, M.; et al. β-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma. Cancer Discov. 2019, 9, 1124–1141. [Google Scholar] [CrossRef] [PubMed]
  72. Hu, J.; Che, L.; Li, L.; Pilo, M.G.; Cigliano, A.; Ribback, S.; Li, X.; Latte, G.; Mela, M.; Evert, M.; et al. Co-activation of AKT and c-Met triggers rapid hepatocellular carcinoma development via the mTORC1/FASN pathway in mice. Sci. Rep. 2016, 6, 20484. [Google Scholar] [CrossRef] [PubMed]
  73. Brodowska, K.; Al-Moujahed, A.; Marmalidou, A.; Zu Horste, M.M.; Cichy, J.; Miller, J.W.; Gragoudas, E.; Vavvas, D.G. The clinically used photosensitizer Verteporfin (VP) inhibits YAP-TEAD and human retinoblastoma cell growth in vitro without light activation. Exp. Eye Res. 2014, 124, 67–73. [Google Scholar] [CrossRef] [Green Version]
  74. Liu-Chittenden, Y.; Huang, B.; Shim, J.S.; Chen, Q.; Lee, S.J.; Anders, R.A.; Liu, J.O.; Pan, D. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 2012, 26, 1300–1305. [Google Scholar] [CrossRef] [Green Version]
  75. Wang, C.; Zhu, X.; Feng, W.; Yu, Y.; Jeong, K.; Guo, W.; Lu, Y.; Mills, G.B. Verteporfin inhibits YAP function through up-regulating 14-3-3σ sequestering YAP in the cytoplasm. Am. J. Cancer Res. 2016, 6, 27–37. [Google Scholar]
  76. Zanconato, F.; Battilana, G.; Cordenonsi, M.; Piccolo, S. YAP/TAZ as therapeutic targets in cancer. Curr. Opin. Pharm. 2016, 29, 26–33. [Google Scholar] [CrossRef] [PubMed]
  77. Zhang, H.; Ramakrishnan, S.K.; Triner, D.; Centofanti, B.; Maitra, D.; Győrffy, B.; Sebolt-Leopold, J.S.; Dame, M.K.; Varani, J.; Brenner, D.E.; et al. Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1. Sci. Signal. 2015, 8, ra98. [Google Scholar] [CrossRef] [Green Version]
  78. Gavini, J.; Dommann, N.; Jakob, M.O.; Keogh, A.; Bouchez, L.C.; Karkampouna, S.; Julio, M.K.; Medova, M.; Zimmer, Y.; Schläfli, A.M.; et al. Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma. Cell Death Dis. 2019, 10, 749. [Google Scholar] [CrossRef] [Green Version]
  79. Zhou, Y.; Wang, Y.; Zhou, W.; Chen, T.; Wu, Q.; Chutturghoon, V.K.; Lin, B.; Geng, L.; Yang, Z.; Zhou, L.; et al. YAP promotes multi-drug resistance and inhibits autophagy-related cell death in hepatocellular carcinoma via the RAC1-ROS-mTOR pathway. Cancer Cell Int. 2019, 19, 179. [Google Scholar] [CrossRef]
  80. Deng, X.; Fang, L. VGLL4 is a transcriptional cofactor acting as a novel tumor suppressor via interacting with TEADs. Am. J. Cancer Res. 2018, 8, 932–943. [Google Scholar]
  81. Jiao, S.; Wang, H.; Shi, Z.; Dong, A.; Zhang, W.; Song, X.; He, F.; Wang, Y.; Zhang, Z.; Wang, W.; et al. A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell 2014, 25, 166–180. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Chen, Q.; Zhou, X.W.; Zhang, A.J.; He, K. ACTN1 supports tumor growth by inhibiting Hippo signaling in hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 2021, 40, 23. [Google Scholar] [CrossRef] [PubMed]
  83. Herman, G.A.; Stevens, C.; Van Dyck, K.; Bergman, A.; Yi, B.; De Smet, M.; Snyder, K.; Hilliard, D.; Tanen, M.; Tanaka, W.; et al. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: Results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin. Pharm. Ther. 2005, 78, 675–688. [Google Scholar] [CrossRef] [PubMed]
  84. Abd El-Fattah, E.E.; Saber, S.; Youssef, M.E.; Eissa, H.; El-Ahwany, E.; Amin, N.A.; Alqarni, M.; Batiha, G.E.; Obaidullah, A.J.; Kaddah, M.M.Y.; et al. AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma. Front. Pharm. 2021, 12, 720173. [Google Scholar] [CrossRef] [PubMed]
  85. Jia, Y.; Wang, Y.; Xie, J. The Hedgehog pathway: Role in cell differentiation, polarity and proliferation. Arch. Toxicol. 2015, 89, 179–191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Varjosalo, M.; Taipale, J. Hedgehog: Functions and mechanisms. Genes Dev. 2008, 22, 2454–2472. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Jeng, K.S.; Jeng, C.J.; Jeng, W.J.; Sheen, I.S.; Li, S.Y.; Leu, C.M.; Tsay, Y.G.; Chang, C.F. Sonic Hedgehog signaling pathway as a potential target to inhibit the progression of hepatocellular carcinoma. Oncol. Lett. 2019, 18, 4377–4384. [Google Scholar] [CrossRef] [Green Version]
  88. Bürglin, T.R. The Hedgehog protein family. Genome Biol. 2008, 9, 241. [Google Scholar] [CrossRef]
  89. Skoda, A.M.; Simovic, D.; Karin, V.; Kardum, V.; Vranic, S.; Serman, L. The role of the Hedgehog signaling pathway in cancer: A comprehensive review. Bosn. J. Basic Med. Sci. 2018, 18, 8–20. [Google Scholar] [CrossRef]
  90. Ding, J.; Li, H.Y.; Zhang, L.; Zhou, Y.; Wu, J. Hedgehog Signaling, a Critical Pathway Governing the Development and Progression of Hepatocellular Carcinoma. Cells 2021, 10, 123. [Google Scholar] [CrossRef]
  91. Wang, Q.; Huang, S.; Yang, L.; Zhao, L.; Yin, Y.; Liu, Z.; Chen, Z.; Zhang, H. Down-regulation of Sonic hedgehog signaling pathway activity is involved in 5-fluorouracil-induced apoptosis and motility inhibition in Hep3B cells. Acta Biochim. Biophys. Sin. 2008, 40, 819–829. [Google Scholar] [CrossRef] [PubMed]
  92. Goetz, S.C.; Anderson, K.V. The primary cilium: A signalling centre during vertebrate development. Nat. Rev. Genet. 2010, 11, 331–344. [Google Scholar] [CrossRef] [PubMed]
  93. Denef, N.; Neubüser, D.; Perez, L.; Cohen, S.M. Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Cell 2000, 102, 521–531. [Google Scholar] [CrossRef] [Green Version]
  94. Machado, M.V.; Diehl, A.M. Hedgehog signalling in liver pathophysiology. J. Hepatol. 2018, 68, 550–562. [Google Scholar] [CrossRef] [Green Version]
  95. Sigafoos, A.N.; Paradise, B.D.; Fernandez-Zapico, M.E. Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease. Cancers 2021, 13, 3410. [Google Scholar] [CrossRef]
  96. Wang, B.; Li, Y. Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. Proc. Natl. Acad. Sci. USA 2006, 103, 33–38. [Google Scholar] [CrossRef] [Green Version]
  97. Pan, Y.; Wang, B. A novel protein-processing domain in Gli2 and Gli3 differentially blocks complete protein degradation by the proteasome. J. Biol. Chem. 2007, 282, 10846–10852. [Google Scholar] [CrossRef] [Green Version]
  98. Niewiadomski, P.; Kong, J.H.; Ahrends, R.; Ma, Y.; Humke, E.W.; Khan, S.; Teruel, M.N.; Novitch, B.G.; Rohatgi, R. Gli protein activity is controlled by multisite phosphorylation in vertebrate Hedgehog signaling. Cell Rep. 2014, 6, 168–181. [Google Scholar] [CrossRef] [Green Version]
  99. Briscoe, J.; Thérond, P.P. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat. Rev. Mol. Cell Biol. 2013, 14, 416–429. [Google Scholar] [CrossRef]
  100. Carballo, G.B.; Honorato, J.R.; de Lopes, G.P.F.; Spohr, T. A highlight on Sonic hedgehog pathway. Cell Commun. Signal. 2018, 16, 11. [Google Scholar] [CrossRef]
  101. Pietrobono, S.; Gagliardi, S.; Stecca, B. Non-canonical Hedgehog Signaling Pathway in Cancer: Activation of GLI Transcription Factors Beyond Smoothened. Front. Genet. 2019, 10, 556. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Barnes, E.A.; Kong, M.; Ollendorff, V.; Donoghue, D.J. Patched1 interacts with cyclin B1 to regulate cell cycle progression. EMBO J. 2001, 20, 2214–2223. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Sicklick, J.K.; Li, Y.X.; Jayaraman, A.; Kannangai, R.; Qi, Y.; Vivekanandan, P.; Ludlow, J.W.; Owzar, K.; Chen, W.; Torbenson, M.S.; et al. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis 2006, 27, 748–757. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Patil, M.A.; Zhang, J.; Ho, C.; Cheung, S.T.; Fan, S.T.; Chen, X. Hedgehog signaling in human hepatocellular carcinoma. Cancer Biol. Ther. 2006, 5, 111–117. [Google Scholar] [CrossRef] [Green Version]
  105. Philips, G.M.; Chan, I.S.; Swiderska, M.; Schroder, V.T.; Guy, C.; Karaca, G.F.; Moylan, C.; Venkatraman, T.; Feuerlein, S.; Syn, W.K.; et al. Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer. PLoS ONE 2011, 6, e23943. [Google Scholar] [CrossRef] [Green Version]
  106. Pasca di Magliano, M.; Hebrok, M. Hedgehog signalling in cancer formation and maintenance. Nat. Rev. Cancer 2003, 3, 903–911. [Google Scholar] [CrossRef]
  107. Che, L.; Yuan, Y.H.; Jia, J.; Ren, J. Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients. Chin. J. Cancer Res. 2012, 24, 323–331. [Google Scholar] [CrossRef] [Green Version]
  108. Huang, S.; He, J.; Zhang, X.; Bian, Y.; Yang, L.; Xie, G.; Zhang, K.; Tang, W.; Stelter, A.A.; Wang, Q.; et al. Activation of the hedgehog pathway in human hepatocellular carcinomas. Carcinogenesis 2006, 27, 1334–1340. [Google Scholar] [CrossRef] [Green Version]
  109. Tada, M.; Kanai, F.; Tanaka, Y.; Tateishi, K.; Ohta, M.; Asaoka, Y.; Seto, M.; Muroyama, R.; Fukai, K.; Imazeki, F.; et al. Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma. Clin. Cancer Res. 2008, 14, 3768–3776. [Google Scholar] [CrossRef] [Green Version]
  110. Chen, J.S.; Li, H.S.; Huang, J.Q.; Zhang, L.J.; Chen, X.L.; Wang, Q.; Lei, J.; Feng, J.T.; Liu, Q.; Huang, X.H. Down-regulation of Gli-1 inhibits hepatocellular carcinoma cell migration and invasion. Mol. Cell. Biochem. 2014, 393, 283–291. [Google Scholar] [CrossRef]
  111. Chen, J.S.; Huang, X.H.; Wang, Q.; Huang, J.Q.; Zhang, L.J.; Chen, X.L.; Lei, J.; Cheng, Z.X. Sonic hedgehog signaling pathway induces cell migration and invasion through focal adhesion kinase/AKT signaling-mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9 in liver cancer. Carcinogenesis 2013, 34, 10–19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Cheng, W.T.; Xu, K.; Tian, D.Y.; Zhang, Z.G.; Liu, L.J.; Chen, Y. Role of Hedgehog signaling pathway in proliferation and invasiveness of hepatocellular carcinoma cells. Int. J. Oncol. 2009, 34, 829–836. [Google Scholar] [CrossRef] [PubMed]
  113. Syn, W.K.; Jung, Y.; Omenetti, A.; Abdelmalek, M.; Guy, C.D.; Yang, L.; Wang, J.; Witek, R.P.; Fearing, C.M.; Pereira, T.A.; et al. Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease. Gastroenterology 2009, 137, 1478–1488.e1478. [Google Scholar] [CrossRef] [Green Version]
  114. Chung, S.I.; Moon, H.; Ju, H.L.; Cho, K.J.; Kim, D.Y.; Han, K.H.; Eun, J.W.; Nam, S.W.; Ribback, S.; Dombrowski, F.; et al. Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model. J. Hepatol. 2016, 64, 618–627. [Google Scholar] [CrossRef] [PubMed]
  115. Michelotti, G.A.; Xie, G.; Swiderska, M.; Choi, S.S.; Karaca, G.; Krüger, L.; Premont, R.; Yang, L.; Syn, W.K.; Metzger, D.; et al. Smoothened is a master regulator of adult liver repair. J. Clin. Investig. 2013, 123, 2380–2394. [Google Scholar] [CrossRef] [Green Version]
  116. Chen, B.; Hu, Z.; Chen, B.; Li, B. Effects and mechanism of Lanthanum Citrate on the proliferation and apoptosis of hepatocellular carcinoma cell line SMMC-7721. Turk. J. Gastroenterol. 2020, 31, 264–271. [Google Scholar] [CrossRef]
  117. Jeng, K.S.; Sheen, I.S.; Jeng, W.J.; Yu, M.C.; Tsai, H.H.; Chang, F.Y.; Su, J.C. Blockade of the sonic hedgehog pathway effectively inhibits the growth of hepatoma in mice: An in vivo study. Oncol. Lett. 2012, 4, 1158–1162. [Google Scholar] [CrossRef]
  118. Arzumanyan, A.; Sambandam, V.; Clayton, M.M.; Choi, S.S.; Xie, G.; Diehl, A.M.; Yu, D.Y.; Feitelson, M.A. Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein. Cancer Res. 2012, 72, 5912–5920. [Google Scholar] [CrossRef] [Green Version]
  119. Tian, H.; He, Z. Anti-hepatoma effect of taccalonolide A through suppression of sonic hedgehog pathway. Artif. Cells Nanomed. Biotechnol. 2020, 48, 939–947. [Google Scholar] [CrossRef]
  120. Harada, K.; Ohashi, R.; Naito, K.; Kanki, K. Hedgehog Signal Inhibitor GANT61 Inhibits the Malignant Behavior of Undifferentiated Hepatocellular Carcinoma Cells by Targeting Non-Canonical GLI Signaling. Int. J. Mol. Sci. 2020, 21, 3126. [Google Scholar] [CrossRef]
  121. Wang, Y.; Han, C.; Lu, L.; Magliato, S.; Wu, T. Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells. Hepatology 2013, 58, 995–1010. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Wang, W.; Smits, R.; Hao, H.; He, C. Wnt/β-Catenin Signaling in Liver Cancers. Cancers 2019, 11, 926. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Stamos, J.L.; Weis, W.I. The β-catenin destruction complex. Cold Spring Harb. Perspect. Biol. 2013, 5, a007898. [Google Scholar] [CrossRef] [PubMed]
  124. He, S.; Tang, S. WNT/β-catenin signaling in the development of liver cancers. Biomed. Pharm. 2020, 132, 110851. [Google Scholar] [CrossRef]
  125. Kim, E.; Lisby, A.; Ma, C.; Lo, N.; Ehmer, U.; Hayer, K.E.; Furth, E.E.; Viatour, P. Promotion of growth factor signaling as a critical function of β-catenin during HCC progression. Nat. Commun. 2019, 10, 1909. [Google Scholar] [CrossRef]
  126. Rao, T.P.; Kühl, M. An updated overview on Wnt signaling pathways: A prelude for more. Circ. Res. 2010, 106, 1798–1806. [Google Scholar] [CrossRef]
  127. Lavergne, E.; Hendaoui, I.; Coulouarn, C.; Ribault, C.; Leseur, J.; Eliat, P.A.; Mebarki, S.; Corlu, A.; Clément, B.; Musso, O. Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin. Oncogene 2011, 30, 423–433. [Google Scholar] [CrossRef] [Green Version]
  128. Glinka, A.; Wu, W.; Delius, H.; Monaghan, A.P.; Blumenstock, C.; Niehrs, C. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 1998, 391, 357–362. [Google Scholar] [CrossRef]
  129. Niehrs, C. Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene 2006, 25, 7469–7481. [Google Scholar] [CrossRef] [Green Version]
  130. Cruciat, C.M.; Niehrs, C. Secreted and transmembrane wnt inhibitors and activators. Cold Spring Harb. Perspect. Biol. 2013, 5, a015081. [Google Scholar] [CrossRef] [Green Version]
  131. Jain, S.; Ghanghas, P.; Rana, C.; Sanyal, S.N. Role of GSK-3β in Regulation of Canonical Wnt/β-catenin Signaling and PI3-K/Akt Oncogenic Pathway in Colon Cancer. Cancer Investig. 2017, 35, 473–483. [Google Scholar] [CrossRef] [PubMed]
  132. Huber, O.; Korn, R.; McLaughlin, J.; Ohsugi, M.; Herrmann, B.G.; Kemler, R. Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. Mech. Dev. 1996, 59, 3–10. [Google Scholar] [CrossRef]
  133. Khalaf, A.M.; Fuentes, D.; Morshid, A.I.; Burke, M.R.; Kaseb, A.O.; Hassan, M.; Hazle, J.D.; Elsayes, K.M. Role of Wnt/β-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance. J. Hepatocell Carcinoma 2018, 5, 61–73. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Qu, B.; Liu, B.R.; Du, Y.J.; Chen, J.; Cheng, Y.Q.; Xu, W.; Wang, X.H. Wnt/β-catenin signaling pathway may regulate the expression of angiogenic growth factors in hepatocellular carcinoma. Oncol. Lett. 2014, 7, 1175–1178. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Tajadura, V.; Hansen, M.H.; Smith, J.; Charles, H.; Rickman, M.; Farrell-Dillon, K.; Claro, V.; Warboys, C.; Ferro, A. β-catenin promotes endothelial survival by regulating eNOS activity and flow-dependent anti-apoptotic gene expression. Cell Death Dis. 2020, 11, 493. [Google Scholar] [CrossRef]
  136. Perugorria, M.J.; Olaizola, P.; Labiano, I.; Esparza-Baquer, A.; Marzioni, M.; Marin, J.J.G.; Bujanda, L.; Banales, J.M. Wnt-β-catenin signalling in liver development, health and disease. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 121–136. [Google Scholar] [CrossRef]
  137. Monga, S.P. β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis. Gastroenterology 2015, 148, 1294–1310. [Google Scholar] [CrossRef] [Green Version]
  138. Essers, M.A.; de Vries-Smits, L.M.; Barker, N.; Polderman, P.E.; Burgering, B.M.; Korswagen, H.C. Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 2005, 308, 1181–1184. [Google Scholar] [CrossRef]
  139. Tang, E.; Wang, Y.; Liu, T.; Yan, B. Gastrin promotes angiogenesis by activating HIF-1α/β-catenin/VEGF signaling in gastric cancer. Gene 2019, 704, 42–48. [Google Scholar] [CrossRef]
  140. Kormish, J.D.; Sinner, D.; Zorn, A.M. Interactions between SOX factors and Wnt/beta-catenin signaling in development and disease. Dev. Dyn. 2010, 239, 56–68. [Google Scholar] [CrossRef] [Green Version]
  141. Inagawa, S.; Itabashi, M.; Adachi, S.; Kawamoto, T.; Hori, M.; Shimazaki, J.; Yoshimi, F.; Fukao, K. Expression and prognostic roles of beta-catenin in hepatocellular carcinoma: Correlation with tumor progression and postoperative survival. Clin. Cancer Res. 2002, 8, 450–456. [Google Scholar] [PubMed]
  142. Lachenmayer, A.; Alsinet, C.; Savic, R.; Cabellos, L.; Toffanin, S.; Hoshida, Y.; Villanueva, A.; Minguez, B.; Newell, P.; Tsai, H.W.; et al. Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clin. Cancer Res. 2012, 18, 4997–5007. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Nhieu, J.T.; Renard, C.A.; Wei, Y.; Cherqui, D.; Zafrani, E.S.; Buendia, M.A. Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am. J. Pathol. 1999, 155, 703–710. [Google Scholar] [CrossRef]
  144. Liu, Y.; Ye, X.; Zhang, J.B.; Ouyang, H.; Shen, Z.; Wu, Y.; Wang, W.; Wu, J.; Tao, S.; Yang, X.; et al. PROX1 promotes hepatocellular carcinoma proliferation and sorafenib resistance by enhancing β-catenin expression and nuclear translocation. Oncogene 2015, 34, 5524–5535. [Google Scholar] [CrossRef] [PubMed]
  145. Vilchez, V.; Turcios, L.; Marti, F.; Gedaly, R. Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment. World J. Gastroenterol. 2016, 22, 823–832. [Google Scholar] [CrossRef] [PubMed]
  146. Krutsenko, Y.; Singhi, A.D.; Monga, S.P. β-Catenin Activation in Hepatocellular Cancer: Implications in Biology and Therapy. Cancers 2021, 13, 1830. [Google Scholar] [CrossRef] [PubMed]
  147. Tao, J.; Xu, E.; Zhao, Y.; Singh, S.; Li, X.; Couchy, G.; Chen, X.; Zucman-Rossi, J.; Chikina, M.; Monga, S.P. Modeling a human hepatocellular carcinoma subset in mice through coexpression of met and point-mutant β-catenin. Hepatology 2016, 64, 1587–1605. [Google Scholar] [CrossRef] [PubMed]
  148. Javanmard, D.; Najafi, M.; Babaei, M.R.; Karbalaie Niya, M.H.; Esghaei, M.; Panahi, M.; Safarnezhad Tameshkel, F.; Tavakoli, A.; Jazayeri, S.M.; Ghaffari, H.; et al. Investigation of CTNNB1 gene mutations and expression in hepatocellular carcinoma and cirrhosis in association with hepatitis B virus infection. Infect. Agent Cancer 2020, 15, 37. [Google Scholar] [CrossRef]
  149. Yang, C.M.; Ji, S.; Li, Y.; Fu, L.Y.; Jiang, T.; Meng, F.D. β-Catenin promotes cell proliferation, migration, and invasion but induces apoptosis in renal cell carcinoma. OncoTargets Ther. 2017, 10, 711–724. [Google Scholar] [CrossRef] [Green Version]
  150. Harding, J.J.; Nandakumar, S.; Armenia, J.; Khalil, D.N.; Albano, M.; Ly, M.; Shia, J.; Hechtman, J.F.; Kundra, R.; El Dika, I.; et al. Prospective Genotyping of Hepatocellular Carcinoma: Clinical Implications of Next-Generation Sequencing for Matching Patients to Targeted and Immune Therapies. Clin. Cancer Res. 2019, 25, 2116–2126. [Google Scholar] [CrossRef] [Green Version]
  151. Satoh, S.; Daigo, Y.; Furukawa, Y.; Kato, T.; Miwa, N.; Nishiwaki, T.; Kawasoe, T.; Ishiguro, H.; Fujita, M.; Tokino, T.; et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat. Genet. 2000, 24, 245–250. [Google Scholar] [CrossRef] [PubMed]
  152. Li, V.S.; Ng, S.S.; Boersema, P.J.; Low, T.Y.; Karthaus, W.R.; Gerlach, J.P.; Mohammed, S.; Heck, A.J.; Maurice, M.M.; Mahmoudi, T.; et al. Wnt signaling through inhibition of β-catenin degradation in an intact Axin1 complex. Cell 2012, 149, 1245–1256. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Dong, B.; Lee, J.S.; Park, Y.Y.; Yang, F.; Xu, G.; Huang, W.; Finegold, M.J.; Moore, D.D. Activating CAR and β-catenin induces uncontrolled liver growth and tumorigenesis. Nat. Commun. 2015, 6, 5944. [Google Scholar] [CrossRef] [Green Version]
  154. Mokkapati, S.; Niopek, K.; Huang, L.; Cunniff, K.J.; Ruteshouser, E.C.; deCaestecker, M.; Finegold, M.J.; Huff, V. β-catenin activation in a novel liver progenitor cell type is sufficient to cause hepatocellular carcinoma and hepatoblastoma. Cancer Res. 2014, 74, 4515–4525. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Savall, M.; Senni, N.; Lagoutte, I.; Sohier, P.; Dentin, R.; Romagnolo, B.; Perret, C.; Bossard, P. Cooperation Between the NRF2 Pathway and Oncogenic β-catenin During HCC Tumorigenesis. Hepatol. Commun. 2021, 5, 1490–1506. [Google Scholar] [CrossRef] [PubMed]
  156. Kim, S.; Jeong, S. Mutation Hotspots in the β-Catenin Gene: Lessons from the Human Cancer Genome Databases. Mol. Cells 2019, 42, 8–16. [Google Scholar] [CrossRef] [PubMed]
  157. Lee, S.A.; Ho, C.; Roy, R.; Kosinski, C.; Patil, M.A.; Tward, A.D.; Fridlyand, J.; Chen, X. Integration of genomic analysis and in vivo transfection to identify sprouty 2 as a candidate tumor suppressor in liver cancer. Hepatology 2008, 47, 1200–1210. [Google Scholar] [CrossRef] [PubMed]
  158. Tward, A.D.; Jones, K.D.; Yant, S.; Cheung, S.T.; Fan, S.T.; Chen, X.; Kay, M.A.; Wang, R.; Bishop, J.M. Distinct pathways of genomic progression to benign and malignant tumors of the liver. Proc. Natl. Acad. Sci. USA 2007, 104, 14771–14776. [Google Scholar] [CrossRef] [Green Version]
  159. Zhang, Y.; Xia, M.; Jin, K.; Wang, S.; Wei, H.; Fan, C.; Wu, Y.; Li, X.; Li, X.; Li, G.; et al. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol. Cancer 2018, 17, 45. [Google Scholar] [CrossRef]
  160. Toh, T.B.; Lim, J.J.; Hooi, L.; Rashid, M.; Chow, E.K. Targeting Jak/Stat pathway as a therapeutic strategy against SP/CD44+ tumorigenic cells in Akt/β-catenin-driven hepatocellular carcinoma. J. Hepatol. 2020, 72, 104–118. [Google Scholar] [CrossRef]
  161. Gurney, A.; Axelrod, F.; Bond, C.J.; Cain, J.; Chartier, C.; Donigan, L.; Fischer, M.; Chaudhari, A.; Ji, M.; Kapoun, A.M.; et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc. Natl. Acad. Sci. USA 2012, 109, 11717–11722. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  162. Le, P.N.; Keysar, S.B.; Miller, B.; Eagles, J.R.; Chimed, T.S.; Reisinger, J.; Gomez, K.E.; Nieto, C.; Jackson, B.C.; Somerset, H.L.; et al. Wnt signaling dynamics in head and neck squamous cell cancer tumor-stroma interactions. Mol. Carcinog. 2019, 58, 398–410. [Google Scholar] [CrossRef] [PubMed]
  163. Le, P.N.; McDermott, J.D.; Jimeno, A. Targeting the Wnt pathway in human cancers: Therapeutic targeting with a focus on OMP-54F28. Pharm. Ther. 2015, 146, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  164. Merle, P.; de la Monte, S.; Kim, M.; Herrmann, M.; Tanaka, S.; Von Dem Bussche, A.; Kew, M.C.; Trepo, C.; Wands, J.R. Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. Gastroenterology 2004, 127, 1110–1122. [Google Scholar] [CrossRef] [PubMed]
  165. Nambotin, S.B.; Lefrancois, L.; Sainsily, X.; Berthillon, P.; Kim, M.; Wands, J.R.; Chevallier, M.; Jalinot, P.; Scoazec, J.Y.; Trepo, C.; et al. Pharmacological inhibition of Frizzled-7 displays anti-tumor properties in hepatocellular carcinoma. J. Hepatol. 2011, 54, 288–299. [Google Scholar] [CrossRef]
  166. Nile, A.H.; de Sousa, E.M.F.; Mukund, S.; Piskol, R.; Hansen, S.; Zhou, L.; Zhang, Y.; Fu, Y.; Gogol, E.B.; Kömüves, L.G.; et al. A selective peptide inhibitor of Frizzled 7 receptors disrupts intestinal stem cells. Nat. Chem. Biol. 2018, 14, 582–590. [Google Scholar] [CrossRef]
  167. Xue, Y.; Chen, C.; Xu, W.; Xu, H.; Zheng, J.; Gu, Y. Downregulation of Frizzled-7 induces the apoptosis of hepatocellular carcinoma cells through inhibition of NF-κB. Oncol. Lett. 2018, 15, 7693–7701. [Google Scholar] [CrossRef]
  168. Wei, W.; Chua, M.S.; Grepper, S.; So, S. Small molecule antagonists of Tcf4/beta-catenin complex inhibit the growth of HCC cells in vitro and in vivo. Int. J. Cancer 2010, 126, 2426–2436. [Google Scholar] [CrossRef]
  169. Yamashita, T.; Budhu, A.; Forgues, M.; Wang, X.W. Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. Cancer Res. 2007, 67, 10831–10839. [Google Scholar] [CrossRef] [Green Version]
  170. Yan, M.; Li, G.; An, J. Discovery of small molecule inhibitors of the Wnt/β-catenin signaling pathway by targeting β-catenin/Tcf4 interactions. Exp. Biol. Med. 2017, 242, 1185–1197. [Google Scholar] [CrossRef] [Green Version]
  171. Shultz, M.D.; Cheung, A.K.; Kirby, C.A.; Firestone, B.; Fan, J.; Chen, C.H.; Chen, Z.; Chin, D.N.; Dipietro, L.; Fazal, A.; et al. Identification of NVP-TNKS656: The use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor. J. Med. Chem. 2013, 56, 6495–6511. [Google Scholar] [CrossRef] [PubMed]
  172. Huang, J.; Qu, Q.; Guo, Y.; Xiang, Y.; Feng, D. Tankyrases/β-catenin Signaling Pathway as an Anti-proliferation and Anti-metastatic Target in Hepatocarcinoma Cell Lines. J. Cancer 2020, 11, 432–440. [Google Scholar] [CrossRef] [PubMed]
  173. Arqués, O.; Chicote, I.; Puig, I.; Tenbaum, S.P.; Argilés, G.; Dienstmann, R.; Fernández, N.; Caratù, G.; Matito, J.; Silberschmidt, D.; et al. Tankyrase Inhibition Blocks Wnt/β-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer. Clin. Cancer Res. 2016, 22, 644–656. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. Ma, L.; Wang, X.; Jia, T.; Wei, W.; Chua, M.S.; So, S. Tankyrase inhibitors attenuate WNT/β-catenin signaling and inhibit growth of hepatocellular carcinoma cells. Oncotarget 2015, 6, 25390–25401. [Google Scholar] [CrossRef] [Green Version]
  175. Weinstein, I.B. Cancer. Addiction to oncogenes-the Achilles heal of cancer. Science 2002, 297, 63–64. [Google Scholar] [CrossRef]
  176. Llovet, J.M.; Villanueva, A.; Lachenmayer, A.; Finn, R.S. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat. Rev. Clin. Oncol. 2015, 12, 408–424. [Google Scholar] [CrossRef]
  177. Fiskus, W.; Sharma, S.; Saha, S.; Shah, B.; Devaraj, S.G.; Sun, B.; Horrigan, S.; Leveque, C.; Zu, Y.; Iyer, S.; et al. Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells. Leukemia 2015, 29, 1267–1278. [Google Scholar] [CrossRef]
  178. Wall, J.A.; Meza-Perez, S.; Scalise, C.B.; Katre, A.; Londoño, A.I.; Turbitt, W.J.; Randall, T.; Norian, L.A.; Arend, R.C. Manipulating the Wnt/β-catenin signaling pathway to promote anti-tumor immune infiltration into the TME to sensitize ovarian cancer to ICB therapy. Gynecol. Oncol. 2021, 160, 285–294. [Google Scholar] [CrossRef]
  179. Institut National de la Santé Et de la Recherche Médicale France. A Pilot Study to Evaluate the Safety of a 3 Weeks Sitagliptin Treatment in HCC Patients Undergoing Liver Resection. Available online: https://clinicaltrials.gov/show/NCT02650427 (accessed on 22 February 2022).
  180. Jason, K.; Sicklick, M.D. LDE225 in Patients with Advanced or Metastatic Hepatocellular Carcinoma and Child-Pugh A/B7 Cirrhosis. Available online: https://clinicaltrials.gov/show/NCT02151864 (accessed on 22 February 2022).
  181. Genentech, I. A Study of Vismodegib in Patients with Advanced Solid Malignancies Including Hepatocellular Carcinoma with Varying Degrees of Renal or Hepatic Function. Available online: https://clinicaltrials.gov/show/NCT01546519 (accessed on 22 February 2022).
  182. OncoMed Pharmaceuticals; Mereo BioPharma. Dose Escalation Study of OMP-54F28 in Combination with Sorafenib in Patients with Hepatocellular Cancer. Available online: https://clinicaltrials.gov/show/NCT02069145 (accessed on 22 February 2022).
  183. Marquardt, J.U. DKN-01 Inhibition in Advanced Liver Cancer. Available online: https://clinicaltrials.gov/show/NCT03645980 (accessed on 22 February 2022).
  184. Childrens Oncology Group. Tegavivint for the Treatment of Recurrent or Refractory Solid Tumors, Including Lymphomas and Desmoid Tumors. Available online: https://clinicaltrials.gov/show/NCT04851119 (accessed on 22 February 2022).
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Figure 1. Schematic illustration of Hippo-YAP/TAZ signaling pathway. A variety of cellular conditions in tissue such as cell density, extracellular matrix (ECM) stiffness, or cell polarity can elicit signals regulating the Hippo signaling cascade. Receptors sensing the cellular conditions have yet to be identified. (A) When the Hippo signaling is turned on, sequential phosphorylation processes by kinase components of the pathway lead to phosphorylation of YAP/TAZ, resulting in cytoplasmic retention or degradation of the transcription factors. (B) When the Hippo signaling is turned off, unphosphorylated YAP/TAZ can translocate into the nucleus, where they interact with TEAD and transcriptionally activate numerous target genes. The Hippo–YAP/TAZ signaling pathway presented in the figure is tightly regulated in hepatocytes, the parenchymal cells in the liver.
Figure 1. Schematic illustration of Hippo-YAP/TAZ signaling pathway. A variety of cellular conditions in tissue such as cell density, extracellular matrix (ECM) stiffness, or cell polarity can elicit signals regulating the Hippo signaling cascade. Receptors sensing the cellular conditions have yet to be identified. (A) When the Hippo signaling is turned on, sequential phosphorylation processes by kinase components of the pathway lead to phosphorylation of YAP/TAZ, resulting in cytoplasmic retention or degradation of the transcription factors. (B) When the Hippo signaling is turned off, unphosphorylated YAP/TAZ can translocate into the nucleus, where they interact with TEAD and transcriptionally activate numerous target genes. The Hippo–YAP/TAZ signaling pathway presented in the figure is tightly regulated in hepatocytes, the parenchymal cells in the liver.
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Figure 2. Schematic illustration of signal transduction by the canonical Hedgehog signaling pathway. (A) In the absence of the ligand, the patched receptor (Ptch) suppresses Smo, leading to the generation of Gli repressor (GliR) by proteolytic cleavage of Gli. GliR suppresses transcription of Hedgehog target genes. (B) Binding of ligands to Ptch relieves the suppression of Smo by the receptor, leading to movement of Smo to primary cilium where it inhibits proteolysis of Gli. Uncleaved and unphosphorylated Gli protein translocates into the nucleus and induces transcription of Hedgehog target genes as Gli transcriptional activator (GliA). Ptch, Patched; Smo, Smoothened; Gli, Glioma-associated oncogene.
Figure 2. Schematic illustration of signal transduction by the canonical Hedgehog signaling pathway. (A) In the absence of the ligand, the patched receptor (Ptch) suppresses Smo, leading to the generation of Gli repressor (GliR) by proteolytic cleavage of Gli. GliR suppresses transcription of Hedgehog target genes. (B) Binding of ligands to Ptch relieves the suppression of Smo by the receptor, leading to movement of Smo to primary cilium where it inhibits proteolysis of Gli. Uncleaved and unphosphorylated Gli protein translocates into the nucleus and induces transcription of Hedgehog target genes as Gli transcriptional activator (GliA). Ptch, Patched; Smo, Smoothened; Gli, Glioma-associated oncogene.
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Figure 3. Schematic illustration of signal transduction by Wnt/ β-catenin signaling pathway. (A) In the absence of the ligand Wnt, β-catenin is degraded via the ubiquitin-mediated proteasome pathway. (B) In the presence of the ligand, β-catenin escapes from β-catenin destruction complex and translocates into the nucleus where it induces transcriptional activation of a plethora of target genes through the interaction with TCF/LEF.
Figure 3. Schematic illustration of signal transduction by Wnt/ β-catenin signaling pathway. (A) In the absence of the ligand Wnt, β-catenin is degraded via the ubiquitin-mediated proteasome pathway. (B) In the presence of the ligand, β-catenin escapes from β-catenin destruction complex and translocates into the nucleus where it induces transcriptional activation of a plethora of target genes through the interaction with TCF/LEF.
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Table
Table 1. Genetically engineered mouse models with dysregulated Hippo-YAP/TAZ signaling.
Table 1. Genetically engineered mouse models with dysregulated Hippo-YAP/TAZ signaling.
GeneMouse ModelPhenotype/Tumor TypeReference
NF2Alb-Cre; NF2 f/fBile duct hamartomas, HCC[43,44]
AVV-Cre; NF2 f/fIncreased ductular structure[45]
Alb-Cre; NF2 f/fHepatomegaly, HCC, CCA[46]
MST1/2Alb-Cre; Mst1/2 f/fHepatomegaly, Dysplasia, Increased cell death[47]
Alb-Cre; Mst1/2 f/fLiver overgrowth, Increased cell proliferation[48]
Alb-Cre; Mst1/2 f/fHepatomegaly, HCC, CCA[49]
Alb-Cre; Mst1-/-; Mst2 f/fIncreased pro-inflammatory cytokines[50]
Ad-Cre; Mst1-/-, Mst2 f/-Hepatomegaly, HCC[51]
Sav1Alb-Cre; Sav1 f/fHepatomegaly, Increased immature progenitor cells[52]
Alb-Cre; Sav1 f/fIncreased cell proliferation, HCC, CCA[49]
Alb-Cre; Sav1 f/fHepatomegaly, HCC, CCA[53]
LATS1/2Alb-Cre; Lats1 f/f; Lats2 f/fBile duct malformation, High lethality[54]
Alb-Cre; Lats1-/-; Lats2 f/fHigh immature BECs proliferation[55]
Alb-Cre; Lats1-/-; Lats2 f/fHepatomegaly, BECs Proliferation[56]
MOB1Alb-Cre; Mob1a f/f; Mob1b-/-Increased cholangiocyte-like cells and oval cells, HCC[57]
YAP/TAZApoE-rtTA; TRE-hYAPHepatomegaly, Increased cell proliferation[58]
pCMV-Cre; Yap f/f, Taz f/fReduced tumor cell proliferation[34]
Alb-Cre; Mst1/2 f/f; Yap+/-Necrosis, Cholestasis, Fibrosis, Swelling of tissue[48]
LAP1-tTA; TetO-YAPS127AHepatomegaly, Nuclei enlargement[59]
AAV-Cre; TetO-YAPS127ARapid liver growth[45]
TAZS89A + HRASG12VTumor stromal activation, HCC[60]
YAPS127A + PIK3CAH1047RHigh lipid hepatocytes, HCC, CCA[61]
Table
Table 2. Development of HCC in murine models expressing destruction-resistant β-catenin and its oncogenic partner.
Table 2. Development of HCC in murine models expressing destruction-resistant β-catenin and its oncogenic partner.
GenesLatencyTumor TypeReference
CMet + ΔN90-β-catenin~12 weeksHCC[158]
NRASG12V + ΔN90-β-catenin~12 weeksHCC[157]
Spry2Y55F + ΔN90-β-catenin~24 weeksHCC[157]
myr-AKT + ΔN90-β-catenin~13 weeksHCC[160]
Table
Table 3. Preclinical studies targeting Wnt/β-catenin signaling in HCC.
Table 3. Preclinical studies targeting Wnt/β-catenin signaling in HCC.
DrugTargetPhaseCell LineMouse ModelReference
Fz7-21FZD7In vitroHepG2, Huh-7Not determined[166]
CGP049090β-catenin/TCFIn vivoHepG2, Hep40, Huh-7Xenograft[168,169]
PFK118-310β-catenin/TCFIn vivoHepG2, Hep40, Huh-7Xenograft[168,169]
PFK115-584β-catenin/TCFIn vivoHepG2, Hep40, Huh-7Xenograft[168,169]
NVP-TNKS656TankyraseIn vitroSMMC-7721, MHHC-97hNot determined[171]
XAV939TankyraseIn vivoHepG2, Hep40, Huh-7Xenograft[174]
Table
Table 4. Currently undergoing clinical trials targeting YAP/TAZ, Hedgehog Wnt/β-catenin signaling in HCC.
Table 4. Currently undergoing clinical trials targeting YAP/TAZ, Hedgehog Wnt/β-catenin signaling in HCC.
DrugTarget SignalingNCT NumberPhaseCurrent StatusReference
SitagliptinYAP/TAZNCT02650427ICompleted[179]
SonidegibHedgehogNCT02151864ICompleted[180]
VismodegibHedgehogNCT01546519ICompleted[181]
OMP-54F28Wnt/β-cateninNCT02069145ICompleted[182]
DKN-01Wnt/β-cateninNCT03645980I/IIRecruiting[183]
BC2059Wnt/β-cateninNCT04851119I/IIRecruiting[184]
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Park, H.; Park, H.; Baek, J.; Moon, H.; Ro, S.W. Target Therapy for Hepatocellular Carcinoma: Beyond Receptor Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors. Biology 2022, 11, 585. https://doi.org/10.3390/biology11040585

AMA Style

Park H, Park H, Baek J, Moon H, Ro SW. Target Therapy for Hepatocellular Carcinoma: Beyond Receptor Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors. Biology. 2022; 11(4):585. https://doi.org/10.3390/biology11040585

Chicago/Turabian Style

Park, Hyunjung, Hyerin Park, Jiyeon Baek, Hyuk Moon, and Simon Weonsang Ro. 2022. "Target Therapy for Hepatocellular Carcinoma: Beyond Receptor Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors" Biology 11, no. 4: 585. https://doi.org/10.3390/biology11040585

APA Style

Park, H., Park, H., Baek, J., Moon, H., & Ro, S. W. (2022). Target Therapy for Hepatocellular Carcinoma: Beyond Receptor Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors. Biology, 11(4), 585. https://doi.org/10.3390/biology11040585

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