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Molecular Mechanisms of Liver Cancer
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Molecular Mechanisms of Liver Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 December 2023) | Viewed by 9852

Special Issue Editors

Prof. Dr. Carmen Berasain

E-Mail Website
Guest Editor
Program of Hepatology, Centre of Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain
Interests: molecular mechanisms of liver disease; gene expression; differentiation; splicing; epigenetics; liver cancer
Special Issues, Collections and Topics in MDPI journals
Dr. María Arechederra

E-Mail Website
Guest Editor
Program of Hepatology, Centre of Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain
Interests: liver cancer; molecular mechanisms of liver carcinogenesis; epigenetics; diagnosis; liquid biopsy

Special Issue Information

Dear Colleagues,

Primary liver cancer has emerged as a neoplasm of increasing incidence in recent years. It mainly includes four types of tumors, hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), hepatoblastoma (HB), and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Although each type of tumor is associated with different cells of origin, etiological agents, genetic and epigenetic mechanisms and crosstalk with the tumor microenvironment, all liver tumors share as common features a late diagnosis, limited therapeutic options and a highly resistance to therapies.

This Special Issue aims to cover the state-of-the-art research on the molecular mechanisms implicated in the development of liver cancers, with both original and review articles. We are interested in in vivo validated molecular studies, performed at tissue and single cell level on, cancer metabolism, cellular des-differentiation and crosstalk, drug resistance, identification of new diagnostic and therapeutic response biomarkers, and proposal of new therapeutic targets.

Submissions are welcome to overview but not limited to those molecular aspects of liver cancer.

Prof. Dr. Carmen Berasain
Dr. María Arechederra
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • hepatocellular carcinoma
  • cholangiocarcinoma
  • hepatoblastoma
  • biomarkers
  • molecular mechanisms
  • targeted-therapy for liver cancer

Published Papers (6 papers)

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Research

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20 pages, 4185 KiB  
Article
Establishment and Validation of Novel Prognostic Subtypes in Hepatocellular Carcinoma Based on Bile Acid Metabolism Gene Signatures Using Bulk and Single-Cell RNA-Seq Data
by Yimo Qu, Xiaocheng Gong, Ziyuan Zhao, Zimei Zhang, Qian Zhang, Yuting Huang, Qingsong Xie, Yunfei Liu, Jinfen Wei and Hongli Du
Int. J. Mol. Sci. 2024, 25(2), 919; https://doi.org/10.3390/ijms25020919 - 11 Jan 2024
Viewed by 1236
Abstract
Hepatocellular carcinoma (HCC) is a highly detrimental cancer type and has limited therapeutic options, posing significant threats to human health. The development of HCC has been associated with a disorder in bile acid (BA) metabolism. In this study, we employed an integrative approach, [...] Read more.
Hepatocellular carcinoma (HCC) is a highly detrimental cancer type and has limited therapeutic options, posing significant threats to human health. The development of HCC has been associated with a disorder in bile acid (BA) metabolism. In this study, we employed an integrative approach, combining various datasets and omics analyses, to comprehensively characterize the tumor microenvironment in HCC based on genes related to BA metabolism. Our analysis resulted in the classification of HCC samples into four subtypes (C1, C2a, C2b, and C3). Notably, subtype C2a, characterized by the highest bile acid metabolism score (BAMS), exhibited the highest survival probability. This subtype also demonstrated increased immune cell infiltration, lower cell cycle scores, reduced AFP levels, and a lower risk of metastasis compared to subtypes C1 and C3. Subtype C1 displayed poorer survival probability and elevated cell cycle scores. Importantly, the identified subtypes based on BAMS showed potential relevance to the gene expression of drug targets in currently approved drugs and those under clinical research. Genes encoding VEGFR (FLT4 and KDR) and MET were elevated in C2, while genes such as TGFBR1, TGFB1, ADORA3, SRC, BRAF, RET, FLT3, KIT, PDGFRA, and PDGFRB were elevated in C1. Additionally, FGFR2 and FGFR3, along with immune target genes including PDCD1 and CTLA4, were higher in C3. This suggests that subtypes C1, C2, and C3 might represent distinct potential candidates for TGFB1 inhibitors, VEGFR inhibitors, and immune checkpoint blockade treatments, respectively. Significantly, both bulk and single-cell transcriptome analyses unveiled a negative correlation between BA metabolism and cell cycle-related pathways. In vitro experiments further confirmed that the treatment of HCC cell lines with BA receptor agonist ursodeoxycholic acid led to the downregulation of the expression of cell cycle-related genes. Our findings suggest a plausible involvement of BA metabolism in liver carcinogenesis, potentially mediated through the regulation of tumor cell cycles and the immune microenvironment. This preliminary understanding lays the groundwork for future investigations to validate and elucidate the specific mechanisms underlying this potential association. Furthermore, this study provides a novel foundation for future precise molecular typing and the design of systemic clinical trials for HCC therapy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Liver Cancer)
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17 pages, 7573 KiB  
Article
FARSB Facilitates Hepatocellular Carcinoma Progression by Activating the mTORC1 Signaling Pathway
by Yaofeng Wang, Gengqiao Wang, Shaobo Hu, Chuanzheng Yin, Peng Zhao, Xing Zhou, Shuyu Shao, Ran Liu, Wenjun Hu, Gang Logan Liu, Wenbo Ke and Zifang Song
Int. J. Mol. Sci. 2023, 24(23), 16709; https://doi.org/10.3390/ijms242316709 - 24 Nov 2023
Viewed by 1166
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality. Human phenylalanine tRNA synthetase (PheRS) comprises two α catalytic subunits encoded by the FARSA gene and two β regulatory subunits encoded by the FARSB gene. FARSB is a potential oncogene, but no [...] Read more.
Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality. Human phenylalanine tRNA synthetase (PheRS) comprises two α catalytic subunits encoded by the FARSA gene and two β regulatory subunits encoded by the FARSB gene. FARSB is a potential oncogene, but no experimental data show the relationship between FARSB and HCC progression. We found that the high expression of FARSB in liver cancer is closely related to patients’ low survival and poor prognosis. In liver cancer cells, the mRNA and protein expression levels of FARSB are increased and promote cell proliferation and migration. Mechanistically, FARSB activates the mTOR complex 1 (mTORC1) signaling pathway by binding to the component Raptor of the mTORC1 complex to play a role in promoting cancer. In addition, we found that FARSB can inhibit erastin-induced ferroptosis by regulating the mTOR signaling pathway, which may be another mechanism by which FARSB promotes HCC progression. In summary, FARSB promotes HCC progression and is associated with the poor prognosis of patients. FARSB is expected to be a biomarker for early screening and treatment of HCC. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Liver Cancer)
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13 pages, 3345 KiB  
Article
Prognostic and Predictive Utility of GPD1L in Human Hepatocellular Carcinoma
by Philip K. H. Leung, Bibek Das, Xiaoyu Cheng and Munir Tarazi
Int. J. Mol. Sci. 2023, 24(17), 13113; https://doi.org/10.3390/ijms241713113 - 23 Aug 2023
Viewed by 1400
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. GPD1L, a member of the glycerol-3-phosphate dehydrogenase family, has emerged as a potential tumour suppressor gene, with high expression associated with a favourable prognosis in various cancers. Despite an intriguing inverse relationship [...] Read more.
Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. GPD1L, a member of the glycerol-3-phosphate dehydrogenase family, has emerged as a potential tumour suppressor gene, with high expression associated with a favourable prognosis in various cancers. Despite an intriguing inverse relationship observed with HCC, the precise role and underlying function of GPD1L in HCC remain poorly understood. Here, we aimed to investigate the prognostic significance, molecular characteristics, and predictive potential of GPD1L overexpression in HCC. Analysis of independent datasets revealed a significant correlation between high GPD1L expression and poor survival in HCC patients. Spatial and single cell transcriptome datasets confirmed elevated GDP1L expression in tumour tissue compared to adjacent normal tissue. GPD1L exhibited increased expression and promoter demethylation with advancing tumour stage, confirming positive selection during tumorigeneses. GPD1L overexpression was associated with metabolic dysregulation and enrichment of gene sets related to cell cycle control, epithelial-mesenchymal transition, and E2F targets. Moreover, we demonstrated an inverse correlation between GPD1L expression and therapeutic response for three therapeutic agents (PF-562271, Linsitinib, and BMS-754807), highlighting its potential as a predictive biomarker for HCC treatment outcomes. These data provide insights into the prognostic significance, molecular characteristics, and predictive potential of GPD1L in HCC. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Liver Cancer)
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11 pages, 2215 KiB  
Article
Bone Morphogenetic Protein 13 Has Protumorigenic Effects on Hepatocellular Carcinoma Cells In Vitro
by Vanessa Kersten, Tatjana Seitz, Judith Sommer, Wolfgang E. Thasler, Anja Bosserhoff and Claus Hellerbrand
Int. J. Mol. Sci. 2023, 24(13), 11059; https://doi.org/10.3390/ijms241311059 - 4 Jul 2023
Viewed by 1306
Abstract
Activated hepatic stellate cells (HSCs) play a key role in hepatic fibrosis and, thus, build the “soil” for hepatocarcinogenesis. Furthermore, HSCs are known to promote the progression of hepatocellular carcinoma (HCC), but the molecular mechanisms are only incompletely understood. Recently, we newly described [...] Read more.
Activated hepatic stellate cells (HSCs) play a key role in hepatic fibrosis and, thus, build the “soil” for hepatocarcinogenesis. Furthermore, HSCs are known to promote the progression of hepatocellular carcinoma (HCC), but the molecular mechanisms are only incompletely understood. Recently, we newly described the expression of bone morphogenetic protein 13 (BMP13) by HSCs in fibrotic liver tissue. In addition, BMP13 has mostly been studied in the context of cartilage and bone repair, but not in liver disease or cancer. Thus, we aimed to analyze the expression and function of BMP13 in HCC. Expression analyses revealed high BMP13-expression in activated human HSCs, but not in human HCC-cell-lines. Furthermore, analysis of human HCC tissues showed a significant correlation between BMP13 and α-smooth muscle actin (α-SMA), and immunofluorescence staining confirmed the co-localization of BMP13 and α-SMA, indicating activated HSCs as the cellular source of BMP13 in HCC. Stimulation of HCC cells with recombinant BMP13 increased the expression of the inhibitors of differentiation 1 (ID1) and 2 (ID2), which are known targets of BMP-signaling and cell-cycle promotors. In line with this, BMP13-stimulation caused an induced SMAD 1/5/9 and extracellular signal-regulated kinase (ERK) phosphorylation, as well as reduced expression of cyclin-dependent kinase inhibitors 1A (CDKN1A) and 2A (CDKN2A). Furthermore, stimulation with recombinant BMP13 led to increased proliferation and colony size formation of HCC cells in clonogenicity assays. The protumorigenic effects of BMP13 on HCC cells were almost completely abrogated by the small molecule dorsomorphin 1 (DMH1), which selectively blocks the intracellular kinase domain of ALK2 and ALK3, indicating that BMP13 acts via these BMP type I receptors on HCC cells. In summary, this study newly identifies stroma-derived BMP13 as a potential new tumor promotor in HCC and indicates this secreted growth-factor as a possible novel therapeutic target in HCC. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Liver Cancer)
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Review

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31 pages, 1389 KiB  
Review
New and Old Key Players in Liver Cancer
by Ángel M. Cuesta, Nerea Palao, Paloma Bragado, Alvaro Gutierrez-Uzquiza, Blanca Herrera, Aránzazu Sánchez and Almudena Porras
Int. J. Mol. Sci. 2023, 24(24), 17152; https://doi.org/10.3390/ijms242417152 - 5 Dec 2023
Cited by 2 | Viewed by 1440
Abstract
Liver cancer represents a major health problem worldwide with growing incidence and high mortality, hepatocellular carcinoma (HCC) being the most frequent. Hepatocytes are likely the cellular origin of most HCCs through the accumulation of genetic alterations, although hepatic progenitor cells (HPCs) might also [...] Read more.
Liver cancer represents a major health problem worldwide with growing incidence and high mortality, hepatocellular carcinoma (HCC) being the most frequent. Hepatocytes are likely the cellular origin of most HCCs through the accumulation of genetic alterations, although hepatic progenitor cells (HPCs) might also be candidates in specific cases, as discussed here. HCC usually develops in a context of chronic inflammation, fibrosis, and cirrhosis, although the role of fibrosis is controversial. The interplay between hepatocytes, immune cells and hepatic stellate cells is a key issue. This review summarizes critical aspects of the liver tumor microenvironment paying special attention to platelets as new key players, which exert both pro- and anti-tumor effects, determined by specific contexts and a tight regulation of platelet signaling. Additionally, the relevance of specific signaling pathways, mainly HGF/MET, EGFR and TGF-β is discussed. HGF and TGF-β are produced by different liver cells and platelets and regulate not only tumor cell fate but also HPCs, inflammation and fibrosis, these being key players in these processes. The role of C3G/RAPGEF1, required for the proper function of HGF/MET signaling in HCC and HPCs, is highlighted, due to its ability to promote HCC growth and, regulate HPC fate and platelet-mediated actions on liver cancer. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Liver Cancer)
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20 pages, 1395 KiB  
Review
Primary Liver Cancers: Connecting the Dots of Cellular Studies and Epidemiology with Metabolomics
by Shoma Berkemeyer
Int. J. Mol. Sci. 2023, 24(3), 2409; https://doi.org/10.3390/ijms24032409 - 26 Jan 2023
Cited by 2 | Viewed by 2705
Abstract
Liver cancers are rising worldwide. Between molecular and epidemiological studies, a research gap has emerged which might be amenable to the technique of metabolomics. This review investigates the current understanding of liver cancer’s trends, etiology and its correlates with existing literature for hepatocellular [...] Read more.
Liver cancers are rising worldwide. Between molecular and epidemiological studies, a research gap has emerged which might be amenable to the technique of metabolomics. This review investigates the current understanding of liver cancer’s trends, etiology and its correlates with existing literature for hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA) and hepatoblastoma (HB). Among additional factors, the literature reports dysfunction in the tricarboxylic acid metabolism, primarily for HB and HCC, and point mutations and signaling for CCA. All cases require further investigation of upstream and downstream events. All liver cancers reported dysfunction in the WNT/β-catenin and P13K/AKT/mTOR pathways as well as changes in FGFR. Metabolites of IHD1, IDH2, miRNA, purine, Q10, lipids, phosphatidylcholine, phosphatidylethanolamine, acylcarnitine, 2-HG and propionyl-CoA emerged as crucial and there was an attempt to elucidate the WNT/β-catenin and P13K/AKT/mTOR pathways metabolomically. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Liver Cancer)
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