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21 pages, 3173 KiB

Open AccessArticle

Integrative Evaluation of the Clinical Significance Underlying Protein Arginine Methyltransferases in Hepatocellular Carcinoma

by Yikun Jiang, Shibo Wei, Jin-Mo Koo, Hea-Ju Kim, Wonyoung Park, Yan Zhang, He Guo, Ki-Tae Ha, Chang-Myung Oh, Jong-Sun Kang, Jee-Heon Jeong, Dongryeol Ryu, Kyeong-Jin Kim and Yunju Jo

Cancers 2023, 15(16), 4183; https://doi.org/10.3390/cancers15164183 - 20 Aug 2023

Cited by 3 | Viewed by 1720

Abstract

HCC is a major contributor to cancer-related mortality worldwide. Curative treatments are available for a minority of patients diagnosed at early stages; however, only a few multikinase inhibitors are available and are marginally effective in advanced cases, highlighting the need for novel therapeutic [...] Read more.

HCC is a major contributor to cancer-related mortality worldwide. Curative treatments are available for a minority of patients diagnosed at early stages; however, only a few multikinase inhibitors are available and are marginally effective in advanced cases, highlighting the need for novel therapeutic targets. One potential target is the protein arginine methyltransferase, which catalyzes various forms of arginine methylation and is often overexpressed in various cancers. However, the diverse expression patterns and clinical values of PRMTs in HCC remain unclear. In the present study, we evaluated the transcriptional expression of PRMTs in HCC cohorts using publicly available datasets. Our results revealed a significant association between PRMTs and prognosis in HCC patients with diverse clinical characteristics and backgrounds. This highlights the promising potential of PRMTs as prognostic biomarkers in patients with HCC. In particular, single-cell RNA (scRNA) sequencing analysis coupled with another human cohort study highlighted the pivotal role of PRMT1 in HCC progression, particularly in the context of Tex. Translating these findings into specific therapeutic decisions may address the unmet therapeutic needs of patients with HCC. Full article

(This article belongs to the Special Issue Prognostic and Predictive Biomarkers in Hepatocellular Carcinoma)

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16 pages, 4085 KiB

Open AccessArticle

Tumor Endothelial Cells-Associated Integrin Alpha-6 as a Promising Biomarker for Early Detection and Prognosis of Hepatocellular Carcinoma

by Hyung Seok Kim, Jung Hwan Yoon, Geum Ok Baek, Moon Gyeong Yoon, Ji Eun Han, Hyo Jung Cho, Soon Sun Kim, Jee-Yeong Jeong, Jae Youn Cheong and Jung Woo Eun

Cancers 2023, 15(16), 4156; https://doi.org/10.3390/cancers15164156 - 17 Aug 2023

Cited by 2 | Viewed by 1670

Abstract

HCC remains a lethal cancer type, with early detection being critical for improved patient outcomes. This study introduces a comprehensive methodological approach to identify the ITGA6 gene as a potential blood marker for early HCC (eHCC) detection. We initially analyzed the GSE114564 dataset [...] Read more.

HCC remains a lethal cancer type, with early detection being critical for improved patient outcomes. This study introduces a comprehensive methodological approach to identify the ITGA6 gene as a potential blood marker for early HCC (eHCC) detection. We initially analyzed the GSE114564 dataset encompassing various stages of liver disease, identifying 972 differentially expressed genes in HCC. A refined analysis yielded 59 genes specifically differentially expressed in early HCC, including ITGA6. Subsequent validation in multiple datasets confirmed the consistent upregulation of ITGA6 in HCC. In addition, when analyzing progression-free survival (PFS) within the entire patient cohort and overall survival (OS) specifically among patients classified as tumor grade G1, the group of patients characterized by high expression levels of ITGA6 displayed an elevated risk ratio in relation to prognosis. Further analyses demonstrated the predominant expression of ITGA6 in TECs and its enrichment in angiogenesis-related pathways. Additionally, positive correlations were found between ITGA6 expression and pro-tumorigenic immune cells, but not with anti-tumorigenic immune cells. Our study elucidates the potential of ITGA6 as a blood-based marker for HCC early detection and diagnosis and its complex interplay with the tumor microenvironment. Further research may lead to novel strategies for HCC management and patient care. Full article

(This article belongs to the Special Issue Prognostic and Predictive Biomarkers in Hepatocellular Carcinoma)

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18 pages, 6416 KiB

Open AccessArticle

Gender Differences in a Mouse Model of Hepatocellular Carcinoma Revealed Using Multi-Modal Imaging

by Brian J. Engel, Vincenzo Paolillo, Md. Nasir Uddin, Kristyn A. Gonzales, Kathryn M. McGinnis, Margie N. Sutton, Madhavi Patnana, Brian J. Grindel, Gregory J. Gores, David Piwnica-Worms, Laura Beretta, Federica Pisaneschi, Seth T. Gammon and Steven W. Millward

Cancers 2023, 15(15), 3787; https://doi.org/10.3390/cancers15153787 - 26 Jul 2023

Cited by 1 | Viewed by 1920

Abstract

The worldwide incidence of hepatocellular carcinoma (HCC) continues to rise, in part due to poor diet, limited exercise, and alcohol abuse. Numerous studies have suggested that the loss or mutation of PTEN plays a critical role in HCC tumorigenesis through the activation of [...] Read more.

The worldwide incidence of hepatocellular carcinoma (HCC) continues to rise, in part due to poor diet, limited exercise, and alcohol abuse. Numerous studies have suggested that the loss or mutation of PTEN plays a critical role in HCC tumorigenesis through the activation of the PI3K/Akt signaling axis. The homozygous knockout of PTEN in the livers of mice results in the accumulation of fat (steatosis), inflammation, fibrosis, and eventually progression to HCC. This phenotype bears a striking similarity to non-alcoholic steatohepatitis (NASH) which is thought to occupy an intermediate stage between non-alcoholic fatty liver disease (NAFLD), fibrosis, and HCC. The molecular and physiological phenotypes that manifest during the transition to HCC suggest that molecular imaging could provide a non-invasive screening platform to identify the hallmarks of HCC initiation prior to the presentation of clinical disease. We have carried out longitudinal imaging studies on the liver-specific PTEN knockout mouse model using CT, MRI, and multi-tracer PET to interrogate liver size, steatosis, inflammation, and apoptosis. In male PTEN knockout mice, significant steatosis was observed as early as 3 months using both magnetic resonance spectroscopy (MRS) and computed tomography (CT). Enhanced uptake of the apoptosis tracer ¹⁸F-TBD was also observed in the livers of male PTEN homozygous knockout mice between 3 and 4 months of age relative to heterozygous knockout controls. Liver uptake of the inflammation tracer [¹⁸F]4FN remained relatively low and constant over 7 months in male PTEN homozygous knockout mice, suggesting the suppression of high-energy ROS/RNS with PTEN deletion relative to heterozygous males where the [¹⁸F]4FN liver uptake was elevated at early and late time points. All male PTEN homozygous mice developed HCC lesions by month 10. In contrast to the male cohort, only 20% (2 out of 10) of female PTEN homozygous knockout mice developed HCC lesions by month 10. Steatosis was significantly less pronounced in the female PTEN homozygous knockout mice relative to males and could not accurately predict the eventual occurrence of HCC. As with the males, the [¹⁸F]4FN uptake in female PTEN homozygous knockout mice was low and constant throughout the time course. The liver uptake of ¹⁸F-TBD at 3 and 4.5 months was higher in the two female PTEN knockout mice that would eventually develop HCC and was the most predictive imaging biomarker for HCC in the female cohort. These studies demonstrate the diagnostic and prognostic role of multi-modal imaging in HCC mouse models and provide compelling evidence that disease progression in the PTEN knockout model is highly dependent on gender. Full article

(This article belongs to the Special Issue Prognostic and Predictive Biomarkers in Hepatocellular Carcinoma)

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11 pages, 1503 KiB

Open AccessArticle

Nomogram to Predict the Long-Term Overall Survival of Early-Stage Hepatocellular Carcinoma after Radiofrequency Ablation

by Yuan-Hung Kuo, Tzu-Hsin Huang, Yi-Hao Yen, Sheng-Nan Lu, Jing-Houng Wang, Chao-Hung Hung, Chien-Hung Chen, Ming-Chao Tsai and Kwong-Ming Kee

Cancers 2023, 15(12), 3156; https://doi.org/10.3390/cancers15123156 - 12 Jun 2023

Cited by 9 | Viewed by 1646

Abstract

Our objective was to develop a predictive nomogram that could estimate the long-term survival of patients with very early/early-stage hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA). For this retrospective study, we enrolled 950 patients who initially received curative RFA for HCC at Barcelona [...] Read more.

Our objective was to develop a predictive nomogram that could estimate the long-term survival of patients with very early/early-stage hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA). For this retrospective study, we enrolled 950 patients who initially received curative RFA for HCC at Barcelona Clinic Liver Cancer (BCLC) stages 0 and A between 2002 and 2016. Factors predicting poor survival after RFA were investigated through a Cox proportional hazard model. The nomogram was constructed using the investigated variables influencing overall survival (OS). After a median follow-up time of 6.25 years, 400 patients had died, and 17 patients had received liver transplantation. The 1-,3-,5-,7-, and 10-year OS rates were 94.5%, 73.5%, 57.9%, 45.7%, and 35.8%, respectively. Multivariate analysis showed that age greater than 65 years, albumin-bilirubin (ALBI) grades 2 and 3, AST-to-platelet ratio index (APRI) greater than 1, tumor size larger than 3 cm, diabetes mellitus, end-stage renal disease, and tumor number greater than 1 were significantly associated with poor OS. The nomogram was constructed using these seven variables. The validation results showed a good concordance index of 0.683. When comparing discriminative ability to tumor, node, and metastasis (TNM), BCLC, and Cancer of the Liver Italian Program (CLIP) staging systems, our nomogram had the highest C-index for predicting mortality. This nomogram provides useful information on prognosis post-RFA as a primary treatment and aids physicians in decision-making. Full article

(This article belongs to the Special Issue Prognostic and Predictive Biomarkers in Hepatocellular Carcinoma)

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15 pages, 2701 KiB

Open AccessArticle

The Characteristics and Prognosis of Alpha-Fetoprotein and Des-Gamma-Carboxy Prothrombin Double-Negative Hepatocellular Carcinoma at Baseline in Higher BCLC Stages

by Takakazu Nagahara, Takaaki Sugihara, Takuya Kihara, Suguru Ikeda, Yoshiki Hoshino, Yukako Matsuki, Takuki Sakaguchi, Hiroki Kurumi, Takumi Onoyama, Tomoaki Takata, Tomomitsu Matono, Naoyuki Yamaguchi and Hajime Isomoto

Cancers 2023, 15(2), 390; https://doi.org/10.3390/cancers15020390 - 6 Jan 2023

Cited by 1 | Viewed by 2009

Abstract

Alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP) are widely used as tumor markers to diagnose hepatocellular carcinoma (HCC). Some advanced HCCs demonstrate neither AFP nor DCP. This study investigated the characteristics and prognosis of AFP (<20 ng/mL) and DCP (<40 mAU/ml) double-negative HCC (DNHC) in [...] Read more.

Alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP) are widely used as tumor markers to diagnose hepatocellular carcinoma (HCC). Some advanced HCCs demonstrate neither AFP nor DCP. This study investigated the characteristics and prognosis of AFP (<20 ng/mL) and DCP (<40 mAU/ml) double-negative HCC (DNHC) in higher-stage HCC. Between April 2012 and March 2022, 419 consecutive patients were enrolled with newly diagnosed HCC and 372 patients were selected that were diagnosed by histopathology and/or imaging. AFP-negative, DCP-negative, and double-negative HCC were identified in 262 patients (70.4%), 143 patients (38.2%), and 120 patients (32.3%), respectively. In higher-BCLC stages (BCLC-B, C, and D), 17 patients (14.7%) were DNHC. Although there was no difference in BCLC staging, there were more cases under TNM Stage III in DNHC (71.0% vs. 41.4%, p = 0.026). The median maximum tumor diameter was smaller in DNHC [3.2 (1.8–5.0) vs. 5.5 (3.5–9.0) cm, p = 0.001] and their median survival time was significantly better, even in higher-stage HCC [47.0 (24.0–84.0) vs. 19.0 (14.0–30.0) months, p = 0.027). DNHC in higher-BCLC stage HCC is independent of BCLC staging, characterized by a tumor diameter < 5 cm, and is treatable with a good prognosis. Full article

(This article belongs to the Special Issue Prognostic and Predictive Biomarkers in Hepatocellular Carcinoma)

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Review

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29 pages, 2428 KiB

Open AccessReview

Recent Insights into the Biomarkers, Molecular Targets and Mechanisms of Non-Alcoholic Steatohepatitis-Driven Hepatocarcinogenesis

by Anna Kakehashi, Shugo Suzuki and Hideki Wanibuchi

Cancers 2023, 15(18), 4566; https://doi.org/10.3390/cancers15184566 - 14 Sep 2023

Cited by 6 | Viewed by 2352

Abstract

Non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (NASH) are chronic hepatic conditions leading to hepatocellular carcinoma (HCC) development. According to the recent “multiple-parallel-hits hypothesis”, NASH could be caused by abnormal metabolism, accumulation of lipids, mitochondrial dysfunction, [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (NASH) are chronic hepatic conditions leading to hepatocellular carcinoma (HCC) development. According to the recent “multiple-parallel-hits hypothesis”, NASH could be caused by abnormal metabolism, accumulation of lipids, mitochondrial dysfunction, and oxidative and endoplasmic reticulum stresses and is found in obese and non-obese patients. Recent translational research studies have discovered new proteins and signaling pathways that are involved not only in the development of NAFLD but also in its progression to NASH, cirrhosis, and HCC. Nevertheless, the mechanisms of HCC developing from precancerous lesions have not yet been fully elucidated. Now, it is of particular importance to start research focusing on the discovery of novel molecular pathways that mediate alterations in glucose and lipid metabolism, which leads to the development of liver steatosis. The role of mTOR signaling in NASH progression to HCC has recently attracted attention. The goals of this review are (1) to highlight recent research on novel genetic and protein contributions to NAFLD/NASH; (2) to investigate how recent scientific findings might outline the process that causes NASH-associated HCC; and (3) to explore the reliable biomarkers/targets of NAFLD/NASH-associated hepatocarcinogenesis. Full article

(This article belongs to the Special Issue Prognostic and Predictive Biomarkers in Hepatocellular Carcinoma)

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18 pages, 607 KiB

Open AccessReview

Clinical Significance of Nectins in HCC and Other Solid Malignant Tumors: Implications for Prognosis and New Treatment Opportunities—A Systematic Review

by Jakub Klekowski, Dorota Zielińska, Adriana Hofman, Natalia Zajdel, Paweł Gajdzis and Mariusz Chabowski

Cancers 2023, 15(15), 3983; https://doi.org/10.3390/cancers15153983 - 5 Aug 2023

Cited by 4 | Viewed by 2058

Abstract

The nectin family comprises four proteins, nectin-1 to -4, which act as cell adhesion molecules. Nectins have various regulatory functions in the immune system and can be upregulated or decreased in different tumors. The literature research was conducted manually by the authors using [...] Read more.

The nectin family comprises four proteins, nectin-1 to -4, which act as cell adhesion molecules. Nectins have various regulatory functions in the immune system and can be upregulated or decreased in different tumors. The literature research was conducted manually by the authors using the PubMed database by searching articles published before 2023 with the combination of several nectin-related keywords. A total of 43 studies were included in the main section of the review. Nectins-1–3 have different expressions in tumors. Both the loss of expression and overexpression could be negative prognostic factors. Nectin-4 is the best characterized and the most consistently overexpressed in various tumors, which generally correlates with a worse prognosis. New treatments based on targeting nectin-4 are currently being developed. Enfortumab vedotin is a potent antibody–drug conjugate approved for use in therapy against urothelial carcinoma. Few reports focus on hepatocellular carcinoma, which leaves room for further studies comparing the utility of nectins with commonly used markers. Full article

(This article belongs to the Special Issue Prognostic and Predictive Biomarkers in Hepatocellular Carcinoma)

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23 pages, 406 KiB

Open AccessReview

Prognostic Significance of Serum Albumin Level and Albumin-Based Mono- and Combination Biomarkers in Patients with Hepatocellular Carcinoma

by Long-Bin Jeng, Wen-Ling Chan and Chiao-Fang Teng

Cancers 2023, 15(4), 1005; https://doi.org/10.3390/cancers15041005 - 4 Feb 2023

Cited by 11 | Viewed by 2763

Abstract

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. Although many surgical and nonsurgical therapeutic options have been established for treating HCC, the overall prognosis for HCC patients receiving different treatment modalities remains inadequate, which causes HCC to remain among the [...] Read more.

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. Although many surgical and nonsurgical therapeutic options have been established for treating HCC, the overall prognosis for HCC patients receiving different treatment modalities remains inadequate, which causes HCC to remain among the most life-threatening human cancers worldwide. Therefore, it is vitally important and urgently needed to develop valuable and independent prognostic biomarkers for the early prediction of poor prognosis in HCC patients, allowing more time for more timely and appropriate treatment to improve the survival of patients. As the most abundant protein in plasma, human serum albumin (ALB) is predominantly expressed by the liver and exhibits a wide variety of essential biological functions. It has been well recognized that serum ALB level is a significant independent biomarker for a broad spectrum of human diseases including cancer. Moreover, ALB has been commonly used as a potent biomaterial and therapeutic agent in clinical settings for the treatment of various human diseases. This review provides a comprehensive summary of the evidence from the up-to-date published literature to underscore the prognostic significance of serum ALB level and various ALB-based mono- and combination biomarkers in the prediction of the prognosis of HCC patients after treatment with different surgical, locoregional, and systemic therapies. Full article

(This article belongs to the Special Issue Prognostic and Predictive Biomarkers in Hepatocellular Carcinoma)

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