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Cells
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Hedgehog Signaling in Development and Cancer
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Hedgehog Signaling in Development and Cancer

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 41907

Special Issue Editor

Dr. Maria Domenica Castellone

E-Mail Website
Guest Editor
Consiglio Nazionale delle Ricerche, Rome, Italy
Interests: cancer; tumor–stroma interaction; signaling pathways; GPCR; kinase receptors; target therapy; thyroid
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The canonical Hh signaling pathway involves the binding of a secreted molecule (Hedgehog, Hh) to a 12-span- protein receptor (Patched, Ptch). In the absence of an Hh ligand, the Ptch receptor inhibits a seven-span-transmembrane receptor (Smoothned, Smo), while upon ligand binding, Ptch releases Smo from its inhibition, triggering a cascade of signaling, culminating in the activation of a family of zinc finger transcription factors glioma-associated oncogene (Gli).

In vertebrates, the Hh pathway is localized at the primary cilium, where it undergoes a dynamic trafficking with Ptch located at the cilium membrane in the absence of Hh ligand and Ptch internalization upon Hh binding, with consequent Smo translocation to the cilium membrane and transduction of downstream Hh signaling.

The Hedgehog pathway represents a key regulator of embryonic development and tissue homeostasis as well as of tissue repair and maintenance of stem cells. Recent studies have demonstrated that Hh signaling is activated in a ligand-independent way in familial cancers such as basal cell carcinoma, medulloblastoma, and rhabdomyosarcoma, as a consequence of genetic aberrations deleting the Ptch inhibitory receptor or activating Smo receptor as well as a consequence of Gli amplification, while in sporadic cancers, Hh pathway activation occurs in a ligand- independent noncanonical way, as a result of a crosstalk with other oncogenic pathways or as a consequence of a ligand-dependent autocrine or paracrine way.

This Special Issue offers an Open Access forum that aims to bring together a collection of original research articles, reviews, and communications on the function of Hh signaling in development, human cancers, and diseases, as well as on the role of Hh signaling molecules as diagnostic, prognostic, and therapeutic targets.

Dr. Maria Domenica Castellone
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Hedgehog signaling
  • tumor–stroma interaction
  • development
  • target therapy

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Related Special Issue

Published Papers (7 papers)

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Research

Jump to: Review

23 pages, 5062 KiB  
Article
Selective Targeting of the Hedgehog Signaling Pathway by PBM Nanoparticles in Docetaxel-Resistant Prostate Cancer
by Santosh Kumar Singh, Jennifer B. Gordetsky, Sejong Bae, Edward P. Acosta, James W. Lillard, Jr. and Rajesh Singh
Cells 2020, 9(9), 1976; https://doi.org/10.3390/cells9091976 - 27 Aug 2020
Cited by 25 | Viewed by 3511
Abstract
An abnormality in hedgehog (Hh) signaling has been implicated in the progression of prostate cancer (PCa) to a more aggressive and therapy-resistant disease. Our assessments of human PCa tissues have shown an overexpression of the Hh pathway molecules, glioma-associated oncogene homolog 1 (GLI-1), [...] Read more.
An abnormality in hedgehog (Hh) signaling has been implicated in the progression of prostate cancer (PCa) to a more aggressive and therapy-resistant disease. Our assessments of human PCa tissues have shown an overexpression of the Hh pathway molecules, glioma-associated oncogene homolog 1 (GLI-1), and sonic hedgehog (SHH). The effect of the natural compound thymoquinone (TQ) in controlling the expression of Hh signaling molecules in PCa was investigated in this study. We generated planetary ball-milled nanoparticles (PBM-NPs) made with a natural polysaccharide, containing TQ, and coated with an RNA aptamer, A10, which binds to prostate-specific membrane antigen (PSMA). We prepared docetaxel-resistant C4-2B-R and LNCaP-R cells with a high expression of Hh, showing the integration of drug resistance and Hh signaling. Compared to free TQ, A10-TQ-PBM-NPs were more effective in controlling the Hh pathway. Our findings reveal an effective treatment strategy to inhibit the Hh signaling pathway, thereby suppressing PCa progression. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Development and Cancer)
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22 pages, 4038 KiB  
Article
Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver
by Luise Spormann, Christiane Rennert, Erik Kolbe, Fritzi Ott, Carolin Lossius, Robert Lehmann, Rolf Gebhardt, Thomas Berg and Madlen Matz-Soja
Cells 2020, 9(8), 1817; https://doi.org/10.3390/cells9081817 - 31 Jul 2020
Cited by 7 | Viewed by 3485
Abstract
In the liver, energy homeostasis is mainly regulated by mechanistic target of rapamycin (mTOR) signalling, which influences relevant metabolic pathways, including lipid metabolism. However, the Hedgehog (Hh) pathway is one of the newly identified drivers of hepatic lipid metabolism. Although the link between [...] Read more.
In the liver, energy homeostasis is mainly regulated by mechanistic target of rapamycin (mTOR) signalling, which influences relevant metabolic pathways, including lipid metabolism. However, the Hedgehog (Hh) pathway is one of the newly identified drivers of hepatic lipid metabolism. Although the link between mTOR and Hh signalling was previously demonstrated in cancer development and progression, knowledge of their molecular crosstalk in healthy liver is lacking. To close this information gap, we used a transgenic mouse model, which allows hepatocyte-specific deletion of the Hh pathway, and in vitro studies to reveal interactions between Hh and mTOR signalling. The study was conducted in male and female mice to investigate sexual differences in the crosstalk of these signalling pathways. Our results reveal that the conditional Hh knockout reduces mitochondrial adenosine triphosphate (ATP) production in primary hepatocytes from female mice and inhibits autophagy in hepatocytes from both sexes. Furthermore, in vitro studies show a synergistic effect of cyclopamine and rapamycin on the inhibition of mTor signalling and oxidative respiration in primary hepatocytes from male and female C57BL/6N mice. Overall, our results demonstrate that the impairment of Hh signalling influences mTOR signalling and therefore represses oxidative phosphorylation and autophagy. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Development and Cancer)
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26 pages, 7021 KiB  
Article
Inhibition of Non-Small Cell Lung Cancer Cells by Oxy210, an Oxysterol-Derivative that Antagonizes TGFβ and Hedgehog Signaling
by Frank Stappenbeck, Feng Wang, Liu-Ya Tang, Ying E. Zhang and Farhad Parhami
Cells 2019, 8(10), 1297; https://doi.org/10.3390/cells8101297 - 22 Oct 2019
Cited by 14 | Viewed by 5161
Abstract
Non-Small Cell Lung Cancer (NSCLC) is a common malignancy and leading cause of death by cancer. Metastasis and drug resistance are serious clinical problems encountered in NSCLC therapy. Aberrant activation of the Transforming Growth Factor beta (TGFβ) and Hedgehog (Hh) signal transduction cascades [...] Read more.
Non-Small Cell Lung Cancer (NSCLC) is a common malignancy and leading cause of death by cancer. Metastasis and drug resistance are serious clinical problems encountered in NSCLC therapy. Aberrant activation of the Transforming Growth Factor beta (TGFβ) and Hedgehog (Hh) signal transduction cascades often associate with poor prognosis and aggressive disease progression in NSCLC, as these signals can drive cell proliferation, angiogenesis, metastasis, immune evasion and emergence of drug resistance. Therefore, simultaneous inhibition of TGFβ and Hh signaling, by a single agent, or in combination with other drugs, could yield therapeutic benefits in NSCLC and other cancers. In the current study, we report on the biological and pharmacological evaluation of Oxy210, an oxysterol-based dual inhibitor of TGFβ and Hh signaling. In NSCLC cells, Oxy210 inhibits proliferation, epithelial-mesenchymal transition (EMT) and invasive activity. Combining Oxy210 with Carboplatin (CP) increases the anti-proliferative response to CP and inhibits TGFβ-induced resistance to CP in A549 NSCLC cells. In addition, Oxy210 displays encouraging drug-like properties, including chemical scalability, metabolic stability and oral bioavailability in mice. Unlike other known inhibitors, Oxy210 antagonizes TGFβ and Hh signaling independently of TGFβ receptor kinase inhibition and downstream of Smoothened, respectively. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Development and Cancer)
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Review

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18 pages, 1692 KiB  
Review
Hedgehog Signaling, a Critical Pathway Governing the Development and Progression of Hepatocellular Carcinoma
by Jia Ding, Hui-Yan Li, Li Zhang, Yuan Zhou and Jian Wu
Cells 2021, 10(1), 123; https://doi.org/10.3390/cells10010123 - 11 Jan 2021
Cited by 39 | Viewed by 4757
Abstract
Hedgehog (Hh) signaling is a classic morphogen in controlling embryonic development and tissue repairing. Aberrant activation of Hh signaling has been well documented in liver cancer, including hepatoblastoma, hepatocellular carcinoma (HCC) and cholangiocarcinoma. The present review aims to update the current understanding on [...] Read more.
Hedgehog (Hh) signaling is a classic morphogen in controlling embryonic development and tissue repairing. Aberrant activation of Hh signaling has been well documented in liver cancer, including hepatoblastoma, hepatocellular carcinoma (HCC) and cholangiocarcinoma. The present review aims to update the current understanding on how abnormal Hh signaling molecules modulate initiation, progression, drug resistance and metastasis of HCC. The latest relevant literature was reviewed with our recent findings to provide an overview regarding the molecular interplay and clinical relevance of the Hh signaling in HCC management. Hh signaling molecules are involved in the transformation of pre-carcinogenic lesions to malignant features in chronic liver injury, such as nonalcoholic steatohepatitis. Activation of GLI target genes, such as ABCC1 and TAP1, is responsible for drug resistance in hepatoma cells, with a CD133−/EpCAM− surface molecular profile, and GLI1 and truncated GLI1 account for the metastatic feature of the hepatoma cells, with upregulation of matrix metalloproteinases. A novel bioassay for the Sonic Hh ligand in tissue specimens may assist HCC diagnosis with negative α-fetoprotein and predict early microvascular invasion. In-depth exploration of the Hh signaling deepens our understanding of its molecular modulation in HCC initiation, drug sensitivity and metastasis, and guides precise management of HCC on an individual basis. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Development and Cancer)
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21 pages, 3061 KiB  
Review
Crosstalk of Hedgehog and mTORC1 Pathways
by Lasse Jonsgaard Larsen and Lisbeth Birk Møller
Cells 2020, 9(10), 2316; https://doi.org/10.3390/cells9102316 - 18 Oct 2020
Cited by 42 | Viewed by 6658
Abstract
Hedgehog (Hh) signaling and mTOR signaling, essential for embryonic development and cellular metabolism, are both coordinated by the primary cilium. Observations from cancer cells strongly indicate crosstalk between Hh and mTOR signaling. This hypothesis is supported by several studies: Evidence points to a [...] Read more.
Hedgehog (Hh) signaling and mTOR signaling, essential for embryonic development and cellular metabolism, are both coordinated by the primary cilium. Observations from cancer cells strongly indicate crosstalk between Hh and mTOR signaling. This hypothesis is supported by several studies: Evidence points to a TGFβ-mediated crosstalk; Increased PI3K/AKT/mTOR activity leads to increased Hh signaling through regulation of the GLI transcription factors; increased Hh signaling regulates mTORC1 activity positively by upregulating NKX2.2, leading to downregulation of negative mTOR regulators; GSK3 and AMPK are, as members of both signaling pathways, potentially important links between Hh and mTORC1 signaling; The kinase DYRK2 regulates Hh positively and mTORC1 signaling negatively. In contrast, both positive and negative regulation of Hh has been observed for DYRK1A and DYRK1B, which both regulate mTORC1 signaling positively. Based on crosstalk observed between cilia, Hh, and mTORC1, we suggest that the interaction between Hh and mTORC1 is more widespread than it appears from our current knowledge. Although many studies focusing on crosstalk have been carried out, contradictory observations appear and the interplay involving multiple partners is far from solved. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Development and Cancer)
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31 pages, 1445 KiB  
Review
Hedgehog Signaling and Truncated GLI1 in Cancer
by Daniel Doheny, Sara G. Manore, Grace L. Wong and Hui-Wen Lo
Cells 2020, 9(9), 2114; https://doi.org/10.3390/cells9092114 - 17 Sep 2020
Cited by 111 | Viewed by 12575
Abstract
The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of [...] Read more.
The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1ΔN and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Development and Cancer)
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18 pages, 2971 KiB  
Review
Fine-Tuning of GLI Activity through Arginine Methylation: Its Mechanisms and Function
by Yoshinori Abe and Nobuyuki Tanaka
Cells 2020, 9(9), 1973; https://doi.org/10.3390/cells9091973 - 26 Aug 2020
Cited by 15 | Viewed by 5016
Abstract
The glioma-associated oncogene (GLI) family consists of GLI1, GLI2, and GLI3 in mammals. This family has important roles in development and homeostasis. To achieve these roles, the GLI family has widespread outputs. GLI activity is therefore strictly regulated at multiple levels, including via [...] Read more.
The glioma-associated oncogene (GLI) family consists of GLI1, GLI2, and GLI3 in mammals. This family has important roles in development and homeostasis. To achieve these roles, the GLI family has widespread outputs. GLI activity is therefore strictly regulated at multiple levels, including via post-translational modifications for context-dependent GLI target gene expression. The protein arginine methyl transferase (PRMT) family is also associated with embryogenesis, homeostasis, and cancer mainly via epigenetic modifications. In the PRMT family, PRMT1, PRMT5, and PRMT7 reportedly regulate GLI1 and GLI2 activity. PRMT1 methylates GLI1 to upregulate its activity and target gene expression. Cytoplasmic PRMT5 methylates GLI1 and promotes GLI1 protein stabilization. Conversely, nucleic PRMT5 interacts with MENIN to suppress growth arrest-specific protein 1 expression, which assists Hedgehog ligand binding to Patched, indirectly resulting in downregulated GLI1 activity. PRMT7-mediated GLI2 methylation upregulates its activity through the dissociation of GLI2 and Suppressor of Fused. Together, PRMT1, PRMT5, and PRMT7 regulate GLI activity at multiple revels. Furthermore, the GLI and PRMT families have strong links with various cancers through cancer stem cell maintenance. Therefore, PRMT-mediated regulation of GLI activity would have important roles in cancer stem cell maintenance. Full article
(This article belongs to the Special Issue Hedgehog Signaling in Development and Cancer)
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