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Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment
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Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment

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 (15 March 2023) | Viewed by 33904

Special Issue Editors

Dr. Cristian Turato

E-Mail Website
Guest Editor
Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
Interests: liver cancer; liver fibrosis; NASH; liver signalling; liver models of disease; oxidative stress
Special Issues, Collections and Topics in MDPI journals
Dr. Stefania Cannito

E-Mail Website
Guest Editor
Department of Clinical and Biological Sciences, University of Torino, 10125 Torino, Italy
Interests: liver disease; cancer research; liver fibrosis; metabolism and liver; oxidative stress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hepatocellular carcinoma (HCC) remains a global health challenge and its incidence is growing worldwide. It is estimated that, by 2025, >1 million individuals will be affected by liver cancer annually. Studies using next-generation sequencing suggest different patterns of HCC evolution and confirm the high molecular heterogeneity in a subset of patients. Moreover, data indicate a fundamental contribution of nonmalignant cells of the tumour microenvironment to cancer clonal evolution. Delineating these dynamics is crucial to improving the treatment of HCC, and particularly to help understand how HCC evolution drives resistance to systemic therapies. Currently, potentially systemic therapies, including immune checkpoint inhibitors, tyrosine kinase inhibitors and monoclonal antibodies, have challenged the use of conventional therapies for HCC. Approximately 50% of patients with HCC are estimated to be exposed to systemic therapies in their lifespan, particularly in advanced stages of the disease, and biomarker-based stratification of patients for optimal response to therapy is an unmet need.

In this Special Issue, I invite you to contribute original and cutting-edge research articles, reviews related to the theme of “Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment”.

Dr. Cristian Turato
Dr. Stefania Cannito
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

  • human hepatocellular carcinoma (HCC)
  • tumour microenvironment
  • biomarkers
  • immunotherapy
  • epigenetic modulators
  • precise medicine
  • combination strategies

Published Papers (12 papers)

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Editorial

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3 pages, 192 KiB  
Editorial
Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment
by Beatrice Foglia, Cristian Turato and Stefania Cannito
Int. J. Mol. Sci. 2023, 24(15), 12224; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241512224 - 31 Jul 2023
Cited by 2 | Viewed by 1552
Abstract
The most common form of primary liver malignancy is hepatocellular carcinoma (HCC) [...] Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment)

Research

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17 pages, 3481 KiB  
Article
SPRED2: A Novel Regulator of Epithelial-Mesenchymal Transition and Stemness in Hepatocellular Carcinoma Cells
by Tong Gao, Xu Yang, Masayoshi Fujisawa, Toshiaki Ohara, Tianyi Wang, Nahoko Tomonobu, Masakiyo Sakaguchi, Teizo Yoshimura and Akihiro Matsukawa
Int. J. Mol. Sci. 2023, 24(5), 4996; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054996 - 05 Mar 2023
Cited by 4 | Viewed by 1552
Abstract
The downregulation of SPRED2, a negative regulator of the ERK1/2 pathway, was previously detected in human cancers; however, the biological consequence remains unknown. Here, we investigated the effects of SPRED2 loss on hepatocellular carcinoma (HCC) cell function. Human HCC cell lines, expressing various [...] Read more.
The downregulation of SPRED2, a negative regulator of the ERK1/2 pathway, was previously detected in human cancers; however, the biological consequence remains unknown. Here, we investigated the effects of SPRED2 loss on hepatocellular carcinoma (HCC) cell function. Human HCC cell lines, expressing various levels of SPRED2 and SPRED2 knockdown, increased ERK1/2 activation. SPRED2-knockout (KO)-HepG2 cells displayed an elongated spindle shape with increased cell migration/invasion and cadherin switching, with features of epithelial–mesenchymal transition (EMT). SPRED2-KO cells demonstrated a higher ability to form spheres and colonies, expressed higher levels of stemness markers and were more resistant to cisplatin. Interestingly, SPRED2-KO cells also expressed higher levels of the stem cell surface markers CD44 and CD90. When CD44+CD90+ and CD44−CD90− populations from WT cells were analyzed, a lower level of SPRED2 and higher levels of stem cell markers were detected in CD44+CD90+ cells. Further, endogenous SPRED2 expression decreased when WT cells were cultured in 3D, but was restored in 2D culture. Finally, the levels of SPRED2 in clinical HCC tissues were significantly lower than those in adjacent non-HCC tissues and were negatively associated with progression-free survival. Thus, the downregulation of SPRED2 in HCC promotes EMT and stemness through the activation of the ERK1/2 pathway, and leads to more malignant phenotypes. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment)
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17 pages, 23193 KiB  
Article
ZNF385A and ZNF346 Serve as Prognostic Biomarkers Associated with an Inflamed Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma
by Qihang Peng, Jin Li, Qian Wu, Pei Wang, Zhongcui Kang, Yiting Deng, Yu Xiao, Peng Zheng, Feng Ge and Ying Chen
Int. J. Mol. Sci. 2023, 24(4), 3155; https://doi.org/10.3390/ijms24043155 - 05 Feb 2023
Cited by 3 | Viewed by 2396
Abstract
Hepatocellular carcinoma (HCC) has a high mortality rate worldwide, and there are still many problems in the early diagnosis, molecular targeted therapy, and immunotherapy. It is necessary to explore valuable diagnostic markers and new therapeutic targets in HCC. Zinc finger protein 385A ( [...] Read more.
Hepatocellular carcinoma (HCC) has a high mortality rate worldwide, and there are still many problems in the early diagnosis, molecular targeted therapy, and immunotherapy. It is necessary to explore valuable diagnostic markers and new therapeutic targets in HCC. Zinc finger protein 385A (ZNF385A) and zinc finger protein 346 (ZNF346) represent a unique class of RNA-binding Cys2 His2 (C2H2) zinc finger proteins that are involved in the regulation of cell cycle and apoptosis, but little is known of their roles in HCC. Based on multiple databases and analysis tools, we explored the expression, clinical relation, prognostic value, possible biological function, and pathways of ZNF385A and ZNF346, and their relationship with immune infiltration. Our results revealed that ZNF385A and ZNF346 were highly expressed and were associated with poor prognosis in HCC. Hepatitis B virus (HBV) infection may lead to the overexpression of ZNF385A and ZNF346, which was accompanied by elevated apoptosis and chronic inflammation. Moreover, ZNF385A and ZNF346 were positively correlated with immune-suppressive cells, inflammatory cytokines, immune checkpoint genes, and poor immunotherapy efficacy. Finally, the knockdown of ZNF385A and ZNF346 was observed to negatively affect the proliferation and migration of HepG2 cells in vitro. In conclusion, ZNF385A and ZNF346 are promising candidate biomarkers for the diagnosis, prognosis, and response to immunotherapy in HCC, and this study may help to understand the tumor microenvironment (TME) of liver cancer, and to develop new therapeutic targets. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment)
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23 pages, 2052 KiB  
Article
Cytotoxic T Cell Expression of Leukocyte-Associated Immunoglobulin-Like Receptor-1 (LAIR-1) in Viral Hepatitis C-Mediated Hepatocellular Carcinoma
by Reham Hammad, Reda Badr Aglan, Shaymaa A. Mohammed, Eman Abu-elnasr Awad, Marwa A. Elsaid, Hanan M. Bedair, Seham K. Khirala, Mohamed A Selim, Asmaa A. Abo Elqasem, Areej Rushdi, Mohamed Ali, Omaima I. Abo-Elkheir, Eman F. Sanad and Nadia M. Hamdy
Int. J. Mol. Sci. 2022, 23(20), 12541; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012541 - 19 Oct 2022
Cited by 7 | Viewed by 2140
Abstract
Virus-related hepatocellular carcinoma (HCC) pathogenesis involves liver inflammation, therefore, despite successful treatment, hepatitis C virus (HCV) may progress to HCC from initiated liver cirrhosis. Cytotoxic T cells (Tcs) are known to be involved in HCV-related cirrhotic complications and HCC pathogenesis. The inhibitory checkpoint [...] Read more.
Virus-related hepatocellular carcinoma (HCC) pathogenesis involves liver inflammation, therefore, despite successful treatment, hepatitis C virus (HCV) may progress to HCC from initiated liver cirrhosis. Cytotoxic T cells (Tcs) are known to be involved in HCV-related cirrhotic complications and HCC pathogenesis. The inhibitory checkpoint leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is expressed on Tcs. Therefore, we aimed to determine whether the Tc expression level of LAIR-1 is associated with HCC progression and to evaluate LAIR-1 expression as a noninvasive biomarker for HCC progression in the context of liver cirrhosis related to HCV genotype 4 (G4) in Egyptian patients’ peripheral venous blood liquid biopsy. A total of 64 patients with HCC and 37 patients with liver cirrhosis were enrolled in this case-controlled study, and their LAIR-1 expression on Tc related to the progression of liver cirrhosis was examined and compared to that of the apparently healthy control group (n = 20). LAIR-1 expression was analyzed using flow cytometry. Results: The HCC group had significantly higher LAIR-1 expression on Tc and percentage of Tc positive for LAIR-1 (LAIR-1+Tc%) than the HCV G4-related liver cirrhosis group. LAIR-1+Tc% was correlated with the HCC surrogate tumor marker AFP (r = 0.367, p = 0.001) and insulin resistance and inflammation prognostic ratios/indices. A receiver operating characteristic (ROC) curve revealed that adding LAIR-1+Tc% to AFP can distinguish HCC transformation in the Egyptian patients’ cohort. Upregulated LAIR-1 expression on Tc could be a potential screening noninvasive molecular marker for chronic inflammatory HCV G4 related liver cirrhosis. Moreover, LAIR-1 expression on Tc may be one of the players involved in the progression of liver cirrhosis to HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment)
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15 pages, 3079 KiB  
Article
Inhibition of eIF6 Activity Reduces Hepatocellular Carcinoma Growth: An In Vivo and In Vitro Study
by Alessandra Scagliola, Annarita Miluzio, Giada Mori, Sara Ricciardi, Stefania Oliveto, Nicola Manfrini and Stefano Biffo
Int. J. Mol. Sci. 2022, 23(14), 7720; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147720 - 13 Jul 2022
Cited by 4 | Viewed by 1829
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipids in the liver. Given the high prevalence of NAFLD, its evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) is of global concern. Therapies for managing NASH-driven HCC can benefit from [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipids in the liver. Given the high prevalence of NAFLD, its evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) is of global concern. Therapies for managing NASH-driven HCC can benefit from targeting factors that play a continuous role in NAFLD evolution to HCC. Recent work has shown that postprandial liver translation exacerbates lipid accumulation through the activity of a translation factor, eukaryotic initiation factor 6 (eIF6). Here, we test the effect of eIF6 inhibition on the progression of HCC. Mice heterozygous for eIF6 express half the level of eIF6 compared to wt mice and are resistant to the formation of HCC nodules upon exposure to a high fat/high sugar diet combined with liver damage. Histology showed that nodules in eIF6 het mice were smaller with reduced proliferation compared to wt nodules. By using an in vitro model of human HCC, we confirm that eIF6 depletion reduces the growth of HCC spheroids. We also tested three pharmacological inhibitors of eIF6 activity—eIFsixty-1, eIFsixty-4, and eIFsixty-6—and all three reduced eIF6 binding to 60S ribosomes and limited the growth of HCC spheroids. Thus, inhibition of eIF6 activity is feasible and limits HCC formation. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment)
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16 pages, 3881 KiB  
Article
Orlistat Resensitizes Sorafenib-Resistance in Hepatocellular Carcinoma Cells through Modulating Metabolism
by Pei-Wei Shueng, Hui-Wen Chan, Wei-Chan Lin, Deng-Yu Kuo and Hui-Yen Chuang
Int. J. Mol. Sci. 2022, 23(12), 6501; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126501 - 10 Jun 2022
Cited by 12 | Viewed by 2290
Abstract
Sorafenib is one of the options for advanced hepatocellular carcinoma treatment and has been shown to extend median overall survival. However, sorafenib resistance often develops a few months after treatment. Hence, developing various strategies to overcome sorafenib resistance and understand the possible mechanisms [...] Read more.
Sorafenib is one of the options for advanced hepatocellular carcinoma treatment and has been shown to extend median overall survival. However, sorafenib resistance often develops a few months after treatment. Hence, developing various strategies to overcome sorafenib resistance and understand the possible mechanisms is urgently needed. We first established sorafenib-resistant hepatocellular carcinoma (HCC) cells. Then, we found that sorafenib-resistant Huh7 cells (Huh7/SR) exhibit higher glucose uptakes and express elevated fatty acid synthesis and glucose metabolism-related proteins than their parental counterparts (Huh7). The current study investigated whether sorafenib resistance could be reversed by suppressing fatty acid synthesis, using a fatty acid synthase (FASN) inhibitor, orlistat, in HCC cells. FASN inhibition-caused changes in protein expressions and cell cycle distribution were analyzed by Western blot and flow cytometry, and changes in glucose uptakes were also evaluated by 18F-FDG uptake. Orlistat remarkably enhanced the cytotoxicity of sorafenib in both Huh7 and Huh7/SR cells, and flow cytometry showed that combination treatment significantly increased the sub-G1 population in both cell lines. Western blot revealed that the combination treatment effectively increased the ratio of Bax/Bcl-2 and decreased expressions of pERK; additionally, the combination treatment also strongly suppressed fatty acid synthesis-related proteins (e.g., FASN and SCD) in both cell lines. Lastly, the 18F-FDG uptake was repressed by the combination treatment in both cell lines. Our results indicated that orlistat-mediated FASN inhibition could overcome sorafenib resistance and enhance cell killing in HCC by changing cell metabolism. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment)
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16 pages, 1827 KiB  
Article
The Serum Hepatitis B Virus Large Surface Protein as High-Risk Recurrence Biomarker for Hepatoma after Curative Surgery
by Hung-Wen Tsai, Yun-Ping Lee, Chia-Jui Yen, Kuang-Hsiung Cheng, Chien-Jung Huang and Wenya Huang
Int. J. Mol. Sci. 2022, 23(10), 5376; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105376 - 11 May 2022
Cited by 5 | Viewed by 1713
Abstract
Chronic hepatitis B (CHB) virus infection is the most important cause of HCC and is also associated with tumor progression. The development of viral biomarkers for HCC prognosis is critical in evaluating relative risks to recurrence in the CHB HCC patients. We report [...] Read more.
Chronic hepatitis B (CHB) virus infection is the most important cause of HCC and is also associated with tumor progression. The development of viral biomarkers for HCC prognosis is critical in evaluating relative risks to recurrence in the CHB HCC patients. We report that the large HBV surface protein (LHBS) expression increased in the tumors, implicating that it played a significant role in tumor development. To detect the LHBS in serum and evaluate its association with HCC progression, we developed a sandwich ELISA method for LHBS. The mouse monoclonal antibodies for the pre-S1, pre-S2, and HBS regions were in-house generated and constructed into a chemiluminescent sandwich ELISA system, which allowed sensitive and quantitative measurement of the protein. Using this ELISA assay, we estimated the expression of LHBS in CHB and HCC patients. We found that the serum LHBS level was correlated with the HBS but not the viral titer in serum, indicating that HBV surface proteins’ expression does not mainly depend on viral replication. Moreover, both serum LHBS and HBS levels were lower in the HCC patients than in the CHB. The liver LHBS signals, detected by immunohistochemical staining, showed significant correlations with the serum LHBS and HBS levels. In addition, the more elevated serum LHBS but not HBS level was significantly associated with cirrhosis and worse disease-free and overall survival rates, based on the multivariate analysis. Conclusion: LHBS plays a specific role in tumor progression and is an independent parameter associated with HCC recurrence. Serum LHBS represents a novel noninvasive biomarker for HCC patients with a worse prognosis after surgery. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment)
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Review

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24 pages, 2630 KiB  
Review
Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses
by Beatrice Foglia, Marc Beltrà, Salvatore Sutti and Stefania Cannito
Int. J. Mol. Sci. 2023, 24(8), 7463; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24087463 - 18 Apr 2023
Cited by 10 | Viewed by 2479
Abstract
Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading causes of cancer-related mortality worldwide and whose incidence varies according to geographical area and ethnicity. Metabolic rewiring was recently introduced as an emerging hallmark able to affect tumor progression [...] Read more.
Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading causes of cancer-related mortality worldwide and whose incidence varies according to geographical area and ethnicity. Metabolic rewiring was recently introduced as an emerging hallmark able to affect tumor progression by modulating cancer cell behavior and immune responses. This review focuses on the recent studies examining HCC’s metabolic traits, with particular reference to the alterations of glucose, fatty acid and amino acid metabolism, the three major metabolic changes that have gained attention in the field of HCC. After delivering a panoramic picture of the peculiar immune landscape of HCC, this review will also discuss how the metabolic reprogramming of liver cancer cells can affect, directly or indirectly, the microenvironment and the function of the different immune cell populations, eventually favoring the tumor escape from immunosurveillance. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment)
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18 pages, 1509 KiB  
Review
Liver Organoids as an In Vitro Model to Study Primary Liver Cancer
by Silvia De Siervi and Cristian Turato
Int. J. Mol. Sci. 2023, 24(5), 4529; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054529 - 25 Feb 2023
Cited by 7 | Viewed by 4766
Abstract
Primary liver cancers (PLC), including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are among the leading causes of cancer-related mortality worldwide. Bi-dimensional in vitro models are unable to recapitulate the key features of PLC; consequently, recent advancements in three-dimensional in vitro systems, such as [...] Read more.
Primary liver cancers (PLC), including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are among the leading causes of cancer-related mortality worldwide. Bi-dimensional in vitro models are unable to recapitulate the key features of PLC; consequently, recent advancements in three-dimensional in vitro systems, such as organoids, opened up new avenues for the development of innovative models for studying tumour’s pathological mechanisms. Liver organoids show self-assembly and self-renewal capabilities, retaining essential aspects of their respective in vivo tissue and allowing modelling diseases and personalized treatment development. In this review, we will discuss the current advances in the field of liver organoids focusing on existing development protocols and possible applications in regenerative medicine and drug discovery. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment)
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21 pages, 1702 KiB  
Review
Emerging Role of Cancer-Associated Fibroblasts in Progression and Treatment of Hepatocellular Carcinoma
by Hikmet Akkız
Int. J. Mol. Sci. 2023, 24(4), 3941; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043941 - 15 Feb 2023
Cited by 14 | Viewed by 3279
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and the fourth leading cause of cancer-related death globally. Tumor cells recruit and remodel various types of stromal and inflammatory cells to form a tumor microenvironment (TME), which encompasses cellular and molecular [...] Read more.
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and the fourth leading cause of cancer-related death globally. Tumor cells recruit and remodel various types of stromal and inflammatory cells to form a tumor microenvironment (TME), which encompasses cellular and molecular entities, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), immune cells, myeloid-derived suppressor cells (MDSCs), immune checkpoint molecules and cytokines that promote cancer cell growth, as well as their drug resistance. HCC usually arises in the context of cirrhosis, which is always associated with an enrichment of activated fibroblasts that are owed to chronic inflammation. CAFs are a major component of the TME, providing physical support in it and secreting various proteins, such as extracellular matrices (ECMs), hepatocyte growth factor (HGF), insulin-like growth factor 1/2 (ILGF1/2) and cytokines that can modulate tumor growth and survival. As such, CAF-derived signaling may increase the pool of resistant cells, thus reducing the duration of clinical responses and increasing the degree of heterogeneity within tumors. Although CAFs are often implicated to be associated with tumor growth, metastasis and drug resistance, several studies have reported that CAFs have significant phenotypic and functional heterogeneity, and some CAFs display antitumor and drug-sensitizing properties. Multiple studies have highlighted the relevance of crosstalk between HCC cells, CAFs and other stromal cells in influence of HCC progression. Although basic and clinical studies partially revealed the emerging roles of CAFs in immunotherapy resistance and immune evasion, a better understanding of the unique functions of CAFs in HCC progression will contribute to development of more effective molecular-targeted drugs. In this review article, molecular mechanisms involved in crosstalk between CAFs, HCC cells and other stromal cells, as well as the effects of CAFs on HCC-cell growth, metastasis, drug resistance and clinical outcomes, are comprehensively discussed. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment)
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20 pages, 2185 KiB  
Review
The Role of PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma Metabolism
by Ling-Yu Tian, Daniel J. Smit and Manfred Jücker
Int. J. Mol. Sci. 2023, 24(3), 2652; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032652 - 31 Jan 2023
Cited by 32 | Viewed by 6034
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. Metabolic reprogramming is considered a new hallmark of cancer, but it remains unclearly described in HCC. The dysregulation of the PI3K/AKT/mTOR signaling pathway is common in HCC and [...] Read more.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. Metabolic reprogramming is considered a new hallmark of cancer, but it remains unclearly described in HCC. The dysregulation of the PI3K/AKT/mTOR signaling pathway is common in HCC and is, therefore, a topic of further research and the concern of developing a novel target for liver cancer therapy. In this review, we illustrate mechanisms by which this signaling network is accountable for regulating HCC cellular metabolism, including glucose metabolism, lipid metabolism, amino acid metabolism, pyrimidine metabolism, and oxidative metabolism, and summarize the ongoing clinical trials based on the inhibition of the PI3K/AKT/mTOR pathway in HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment)
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20 pages, 3244 KiB  
Review
Constitutively Active Androgen Receptor in Hepatocellular Carcinoma
by Emma J. Montgomery, Enming Xing, Moray J. Campbell, Pui-Kai Li, James S. Blachly, Allan Tsung and Christopher C. Coss
Int. J. Mol. Sci. 2022, 23(22), 13768; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232213768 - 09 Nov 2022
Cited by 8 | Viewed by 2314
Abstract
Hepatocellular carcinoma (HCC) is the predominant type of liver cancer and a leading cause of cancer-related death globally. It is also a sexually dimorphic disease with a male predominance both in HCC and in its precursors, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). [...] Read more.
Hepatocellular carcinoma (HCC) is the predominant type of liver cancer and a leading cause of cancer-related death globally. It is also a sexually dimorphic disease with a male predominance both in HCC and in its precursors, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The role of the androgen receptor (AR) in HCC has been well documented; however, AR-targeted therapies have failed to demonstrate efficacy in HCC. Building upon understandings of AR in prostate cancer (PCa), this review examines the role of AR in HCC, non-androgen-mediated mechanisms of induced AR expression, the existence of AR splice variants (AR-SV) in HCC and concludes by surveying current AR-targeted therapeutic approaches in PCa that show potential for efficacy in HCC in light of AR-SV expression. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment)
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