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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 (31 October 2021) | Viewed by 51241

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Dr. Hiroaki Taniguchi

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Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 05-552 Jastrzebiec, Poland
Interests: transcription factors; epigenetics; gene mutation; cancer stem cell; molecular biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Liver cancer is one of the most common cancers and is the leading cause of death worldwide. Since there are no subjective symptoms in the early stages, it is generally at quite advanced stage when it is discovered. Chronic liver damage often sets the stage for the oncogenic transformation of liver cells giving rise to liver cancer. Risk factors for this transformation include excessive smoking, alcohol consumption and hepatitis B and C viral infections, all of which can cause mutations in healthy DNA. These mutations can result in the deregulation of genes involved in controlling cell growth, cell death, and cell differentiation, thereby contributing to liver carcinogenesis. In this special issue, we will try to provide the information which would be beneficial for basic scientists to medical doctors in the field of liver cancer research. We will mainly consider the below listed topics but not limited.

Dr. Hiroaki Taniguchi
Guest Editor

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.

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Keywords

Liver cancer and Mutations/Genetics
Liver cancer and Gene regulation
Liver cancer and Stem cells
Liver cancer and Obesity
Liver cancer and Stress
Liver cancer and Clinical trials/Therapies
Liver cancer and Epigenetic gene regulation
Liver cancer and NASH
Liver cancer and Virus
Liver cancer and Immunology
Liver cancer and 3D environment
Liver cancer and Microbiome

Related Special Issues

Liver Cancer 3.0 in International Journal of Molecular Sciences
Liver Cancer 2.0 in International Journal of Molecular Sciences (9 articles)

Published Papers (12 papers)

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Research

Jump to: Review

12 pages, 1245 KiB

Open AccessArticle

Direct Detection of Glutathione Biosynthesis, Conjugation, Depletion and Recovery in Intact Hepatoma Cells

by Rex E. Jeffries, Shawn M. Gomez, Jeffrey M. Macdonald and Michael P. Gamcsik

Int. J. Mol. Sci. 2022, 23(9), 4733; https://doi.org/10.3390/ijms23094733 - 25 Apr 2022

Cited by 1 | Viewed by 1545

Abstract

Nuclear magnetic resonance (NMR) spectroscopy was used to monitor glutathione metabolism in alginate-encapsulated JM-1 hepatoma cells perfused with growth media containing [3,3′-¹³C₂]-cystine. After 20 h of perfusion with labeled medium, the ¹³C NMR spectrum is dominated by the signal from the ¹³C-labeled glutathione. Once ¹³C-labeled, the high intensity of the glutathione resonance allows the acquisition of subsequent spectra in 1.2 min intervals. At this temporal resolution, the detailed kinetics of glutathione metabolism can be monitored as the thiol alkylating agent monobromobimane (mBBr) is added to the perfusate. The addition of a bolus dose of mBBr results in rapid diminution of the resonance for ¹³C-labeled glutathione due to a loss of this metabolite through alkylation by mBBr. As the glutathione resonance decreases, a new resonance due to the production of intracellular glutathione-bimane conjugate is detectable. After clearance of the mBBr dose from the cells, intracellular glutathione repletion is then observed by a restoration of the ¹³C-glutathione signal along with wash-out of the conjugate. These data demonstrate that standard NMR techniques can directly monitor intracellular processes such as glutathione depletion with a time resolution of approximately < 2 min. Full article

(This article belongs to the Special Issue Liver Cancer)

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12 pages, 2450 KiB

Open AccessArticle

A Critical YAP in Malignancy of HCC Is Regulated by Evodiamine

by Un-Jung Yun, Su-Jin Bae, Yu-Rim Song and Young-Woo Kim

Int. J. Mol. Sci. 2022, 23(3), 1855; https://doi.org/10.3390/ijms23031855 - 6 Feb 2022

Cited by 14 | Viewed by 2502

Abstract

Liver cancer has relatively few early symptoms and is usually diagnosed in the advanced stage. Sorafenib is the only first-line anticancer drug approved by the Food and Drug Administration (FDA) for advanced HCC; however, its use is limited due to resistance. Therefore, the development of new drugs is essential to achieving customized treatment. Many studies have suggested that Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) is associated with metastasis and cancer formation and progression in various cancers. In the present study, YAP was overexpressed in various patient-derived hepatocarcinoma (HCC) tissues. In addition, this study examined whether evodiamine (which has anticancer effects) can inhibit YAP and, if so, modulate HCC. Evodiamine significantly reduced both the YAP level and cell growth of HCC in a dose-dependent manner. Biochemical analysis indicated mitochondria dysfunction-mediated apoptosis to be the cause of the reduction in HCC cell growth by evodiamine. YAP was overexpressed in metastatic HCC tissues as well when compared to primary HCC tissues. Migration and invasion analysis showed that evodiamine has anti-metastatic ability on Hep3B and Huh-7 cells and reduces the level of vimentin, an EMT marker. In conclusion, YAP is a critical target in HCC therapy, and evodiamine can be an effective HCC anticancer drug by reducing the YAP level. Full article

(This article belongs to the Special Issue Liver Cancer)

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22 pages, 6877 KiB

Open AccessArticle

Oncogenic Mutation BRAF V600E Changes Phenotypic Behavior of THLE-2 Liver Cells through Alteration of Gene Expression

by Magdalena Śmiech, Paweł Leszczyński, Christopher Wardell, Piotr Poznański, Mariusz Pierzchała and Hiroaki Taniguchi

Int. J. Mol. Sci. 2022, 23(3), 1548; https://doi.org/10.3390/ijms23031548 - 28 Jan 2022

Cited by 3 | Viewed by 3350

Abstract

The accumulation of mutations in cancer driver genes, such as tumor suppressors or proto-oncogenes, affects cellular homeostasis. Disturbances in the mechanism controlling proliferation cause significant augmentation of cell growth and division due to the loss of sensitivity to the regulatory signals. Nowadays, an increasing number of cases of liver cancer are observed worldwide. Data provided by the International Cancer Genome Consortium (ICGC) have indicated many alterations within gene sequences, whose roles in tumor development are not well understood. A comprehensive analysis of liver cancer (virus-associated hepatocellular carcinoma) samples has identified new and rare mutations in B-Raf proto-oncogene (BRAF) in Japanese HCC patients, as well as BRAF V600E mutations in French HCC patients. However, their function in liver cancer has never been investigated. Here, using functional analysis and next generation sequencing, we demonstrate the tumorigenic effect of BRAF V600E on hepatocytes (THLE-2 cell line). Moreover, we identified genes such as BMP6, CXCL11, IL1B, TBX21, RSAD2, MMP10, and SERPIND1, which are possibly regulated by the BRAF V600E-mediated, mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) signaling pathway. Through several functional assays, we demonstrate that BRAF L537M, D594A, and E648G mutations alone are not pathogenic in liver cancer. The investigation of genome mutations and the determination of their impact on cellular processes and functions is crucial to unraveling the molecular mechanisms of liver cancer development. Full article

(This article belongs to the Special Issue Liver Cancer)

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17 pages, 4362 KiB

Open AccessArticle

AXL Knock-Out in SNU475 Hepatocellular Carcinoma Cells Provides Evidence for Lethal Effect Associated with G2 Arrest and Polyploidization

by Tugce Batur, Ayse Argundogan, Umur Keles, Zeynep Mutlu, Hani Alotaibi, Serif Senturk and Mehmet Ozturk

Int. J. Mol. Sci. 2021, 22(24), 13247; https://doi.org/10.3390/ijms222413247 - 9 Dec 2021

Cited by 4 | Viewed by 2698

Abstract

AXL, a member of the TAM family, is a promising therapeutic target due to its elevated expression in advanced hepatocellular carcinoma (HCC), particularly in association with acquired drug resistance. Previously, RNA interference was used to study its role in cancer, and several phenotypic changes, including attenuated cell proliferation and decreased migration and invasion, have been reported. The mechanism of action of AXL in HCC is elusive. We first studied the AXL expression in HCC cell lines by real-time PCR and western blot and showed its stringent association with a mesenchymal phenotype. We then explored the role of AXL in mesenchymal SNU475 cells by CRISPR-Cas9 mediated gene knock-out. AXL-depleted HCC cells displayed drastic phenotypic changes, including increased DNA damage response, prolongation of doubling time, G2 arrest, and polyploidization in vitro and loss of tumorigenicity in vivo. Pharmacological inhibition of AXL by R428 recapitulated G2 arrest and polyploidy phenotype. These observations strongly suggest that acute loss of AXL in some mesenchymal HCC cells is lethal and points out that its inhibition may represent a druggable vulnerability in AXL-high HCC patients. Full article

(This article belongs to the Special Issue Liver Cancer)

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12 pages, 2659 KiB

Open AccessArticle

Pharmacological Inhibition of Sonic Hedgehog Signaling Suppresses Tumor Development in a Murine Model of Intrahepatic Cholangiocarcinoma

by Kyungjoo Cho, Hyuk Moon, Sang Hyun Seo, Simon Weonsang Ro and Beom Kyung Kim

Int. J. Mol. Sci. 2021, 22(24), 13214; https://doi.org/10.3390/ijms222413214 - 8 Dec 2021

Cited by 5 | Viewed by 3099

Abstract

Cholangiocarcinoma (CCC) is the second most primary liver cancer with an aggressive biological behavior, and its incidence increases steadily. An aberrant up-regulation of the sonic hedgehog signaling pathway has been reported in a variety of hepatic diseases including hepatic inflammation, fibrosis, as well as cancer. In this study, we determined the effect of a sonic hedgehog inhibitor, vismodegib, on the development of CCC. Through database analyses, we found sonic hedgehog signaling was up-regulated in human CCC, based on overexpression of its target genes, GLI1 and GLI2. Further, human CCC cells were highly sensitive to the treatment with vismodegib in vitro. Based on the data, we investigated the in vivo anti-cancer efficacy of vismodegib in CCC employing a murine model of CCC developed by hydrodynamic tail vein injection method. In the murine model, CCC induced by constitutively active forms of TAZ and PI3K exhibited up-regulated sonic hedgehog signaling. Treatment of vismodegib significantly suppressed tumor development in the murine CCC model, based on comparison of gross morphologies and liver weight/body weight. It is expected that pharmacological inhibition of sonic hedgehog signaling would be an effective molecular target therapy for CCC. Full article

(This article belongs to the Special Issue Liver Cancer)

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12 pages, 3820 KiB

Open AccessArticle

Antitumor Effect of Morusin via G1 Arrest and Antiglycolysis by AMPK Activation in Hepatocellular Cancer

by Ah-Reum Cho, Woon-Yi Park, Hyo-Jung Lee, Deok-Yong Sim, Eunji Im, Ji-Eon Park, Chi-Hoon Ahn, Bum-Sang Shim and Sung-Hoon Kim

Int. J. Mol. Sci. 2021, 22(19), 10619; https://doi.org/10.3390/ijms221910619 - 30 Sep 2021

Cited by 17 | Viewed by 2588

Abstract

Though Morusin isolated from the root of Morus alba was known to have antioxidant, anti-inflammatory, antiangiogenic, antimigratory, and apoptotic effects, the underlying antitumor effect of Morusin is not fully understood on the glycolysis of liver cancers. Hence, in the current study, the antitumor mechanism of Morusin was explored in Hep3B and Huh7 hepatocellular carcninomas (HCC) in association with glycolysis and G1 arrest. Herein, Morusin significantly reduced the viability and the number of colonies in Hep3B and Huh7 cells. Moreover, Morusin significantly increased G1 arrest, attenuated the expression of cyclin D1, cyclin D3, cyclin E, cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6) and upregulated p21 and p27 in Hep3B and Huh7 cells. Interestingly, Morusin significantly activated phosphorylation of the adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) but attenuated the expression of the p-mammalian target of protein kinase B (AKT), rapamycin (mTOR), c-Myc, hexokinase 2(HK2), pyruvate kinases type M2 (PKM2), and lactate dehydrogenase (LDH) in Hep3B and Huh7 cells. Consistently, Morusin suppressed lactate, glucose, and adenosine triphosphate (ATP) in Hep3B and Huh7 cells. Conversely, the AMPK inhibitor compound C reduced the ability of Morusin to activate AMPK and attenuate the expression of p-mTOR, HK2, PKM2, and LDH-A and suppressed G1 arrest induced by Morusin in Hep3B cells. Overall, these findings suggest that Morusin exerts an antitumor effect in HCCs via AMPK mediated G1 arrest and antiglycolysis as a potent dietary anticancer candidate. Full article

(This article belongs to the Special Issue Liver Cancer)

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16 pages, 2420 KiB

Open AccessArticle

NRF2 DLG Domain Mutations Identified in Japanese Liver Cancer Patients Affect the Transcriptional Activity in HCC Cell Lines

by Effi Haque, Magdalena Śmiech, Kamila Łuczyńska, Marie France Bouchard, Robert Viger, Hidetoshi Kono, Mariusz Pierzchała and Hiroaki Taniguchi

Int. J. Mol. Sci. 2021, 22(10), 5296; https://doi.org/10.3390/ijms22105296 - 18 May 2021

Cited by 2 | Viewed by 2726

Abstract

Geographically, East Asia had the highest liver cancer burden in 2017. Besides this, liver cancer-related deaths were high in Japan, accounting for 3.90% of total deaths. The development of liver cancer is influenced by several factors, and genetic alteration is one of the critical factors among them. Therefore, the detailed mechanism driving the oncogenic transformation of liver cells needs to be elucidated. Recently, many researchers have focused on investigating the liver cancer genome and identified somatic mutations (MTs) of several transcription factors. In this line, next-generation sequencing of the cancer genome identified that oxidative stress-related transcription factor NRF2 (NFE2L2) is mutated in different cancers, including hepatocellular carcinoma (HCC). Here, we demonstrated that NRF2 DLG motif mutations (NRF2 D29A and L30F), found in Japanese liver cancer patients, upregulate the transcriptional activity of NRF2 in HCC cell lines. Moreover, the transcriptional activity of NRF2 mutations is not suppressed by KEAP1, presumably because NRF2 MTs disturb proper NRF2-KEAP1 binding and block KEAP1-mediated degradation of NRF2. Additionally, we showed that both MTs upregulate the transcriptional activity of NRF2 on the MMP9 promoter in Hepa1-6 and Huh7 cells, suggesting that MT derived gain-of-function of NRF2 may be important for liver tumor progression. We also found that ectopic overexpression of oncogenic BRAF WT and V600E increases the transcriptional activity of NRF2 WT on both the 3xARE reporter and MMP9 promoter. Interestingly, NRF2 D29A and L30F MTs with oncogenic BRAF V600E MT synergistically upregulate the transcription activity of NRF2 on the 3xARE reporter and MMP9 promoter in Hepa1-6 and Huh7 cells. In summary, our findings suggest that MTs in NRF2 have pathogenic effects, and that NRF2 MTs together with oncogenic BRAF V600E MT synergistically cause more aberrant transcriptional activity. The high activity of NRF2 MTs in HCC with BRAF MT warrants further exploration of the potential diagnostic, prognostic, and therapeutic utility of this pathway in HCC. Full article

(This article belongs to the Special Issue Liver Cancer)

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Review

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12 pages, 572 KiB

Open AccessReview

Hepatitis B Virus-Associated Hepatocellular Carcinoma and Chronic Stress

by Nicholas Noverati, Rukaiya Bashir-Hamidu, Dina Halegoua-DeMarzio and Hie-Won Hann

Int. J. Mol. Sci. 2022, 23(7), 3917; https://doi.org/10.3390/ijms23073917 - 1 Apr 2022

Cited by 6 | Viewed by 3799

Abstract

The Hepatitis B virus is one of the most significant hepatocarcinogens globally. The carcinogenic mechanisms of this virus are complex, and may include interactions with the host’s immune system. Certain factors, such as stress on the body, can also potentiate these mechanisms. Stress, although adaptive in an acute form, is deleterious to health when chronic and can both suppress and activate the host’s defense system. In hepatocellular carcinoma, this can lead to tumor initiation and progression. Those that are more prone to stress, or exposed to situations that incite stress, may be at higher risk of developing cancer. Racial disparities, for example, are a source of chronic psychosocial stress in America and predispose minorities to poorer outcomes. As it remains perplexing why some individuals with chronic hepatitis B develop feared complications while others do not, it is important to recognize as many risk factors as possible, including those often overlooked such as chronic stress. Full article

(This article belongs to the Special Issue Liver Cancer)

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20 pages, 818 KiB

Open AccessReview

Therapeutic Vaccines against Hepatocellular Carcinoma in the Immune Checkpoint Inhibitor Era: Time for Neoantigens?

by David Repáraz, Belén Aparicio, Diana Llopiz, Sandra Hervás-Stubbs and Pablo Sarobe

Int. J. Mol. Sci. 2022, 23(4), 2022; https://doi.org/10.3390/ijms23042022 - 11 Feb 2022

Cited by 12 | Viewed by 2934

Abstract

Immune checkpoint inhibitors (ICI) have been used as immunotherapy for hepatocellular carcinoma (HCC) with promising but still limited results. Identification of immune elements in the tumor microenvironment of individual HCC patients may help to understand the correlations of responses, as well as to design personalized therapies for non-responder patients. Immune-enhancing strategies, such as vaccination, would complement ICI in those individuals with poorly infiltrated tumors. The prominent role of responses against mutated tumor antigens (neoAgs) in ICI-based therapies suggests that boosting responses against these epitopes may specifically target tumor cells. In this review we summarize clinical vaccination trials carried out in HCC, the available information on potentially immunogenic neoAgs in HCC patients, and the most recent results of neoAg-based vaccines in other tumors. Despite the low/intermediate mutational burden observed in HCC, data obtained from neoAg-based vaccines in other tumors indicate that vaccines directed against these tumor-specific antigens would complement ICI in a subset of HCC patients. Full article

(This article belongs to the Special Issue Liver Cancer)

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17 pages, 333 KiB

Open AccessReview

Hepatocellular Carcinoma in Chronic Viral Hepatitis: Where Do We Stand?

by Francesco Paolo Russo, Alberto Zanetto, Elisa Pinto, Sara Battistella, Barbara Penzo, Patrizia Burra and Fabio Farinati

Int. J. Mol. Sci. 2022, 23(1), 500; https://doi.org/10.3390/ijms23010500 - 2 Jan 2022

Cited by 33 | Viewed by 3680

Abstract

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death. Although the burden of alcohol- and NASH-related HCC is growing, chronic viral hepatitis (HBV and HCV) remains a major cause of HCC development worldwide. The pathophysiology of viral-related HCC includes liver inflammation, oxidative stress, and deregulation of cell signaling pathways. HBV is particularly oncogenic because, contrary to HCV, integrates in the cell DNA and persists despite virological suppression by nucleotide analogues. Surveillance by six-month ultrasound is recommended in patients with cirrhosis and in “high-risk” patients with chronic HBV infection. Antiviral therapy reduces the risks of development and recurrence of HCC; however, patients with advanced chronic liver disease remain at risk of HCC despite virological suppression/cure and should therefore continue surveillance. Multiple scores have been developed in patients with chronic hepatitis B to predict the risk of HCC development and may be used to stratify individual patient’s risk. In patients with HCV-related liver disease who achieve sustained virological response by direct acting antivirals, there is a strong need for markers/scores to predict long-term risk of HCC. In this review, we discuss the most recent advances regarding viral-related HCC. Full article

(This article belongs to the Special Issue Liver Cancer)

19 pages, 1057 KiB

Open AccessReview

The Curious Case of the HepG2 Cell Line: 40 Years of Expertise

by Viktoriia A. Arzumanian, Olga I. Kiseleva and Ekaterina V. Poverennaya

Int. J. Mol. Sci. 2021, 22(23), 13135; https://doi.org/10.3390/ijms222313135 - 4 Dec 2021

Cited by 92 | Viewed by 14876

Abstract

Liver cancer is the third leading cause of cancer death worldwide. Representing such a dramatic impact on our lives, liver cancer is a significant public health concern. Sustainable and reliable methods for preventing and treating liver cancer require fundamental research on its molecular mechanisms. Cell lines are treated as in vitro equivalents of tumor tissues, making them a must-have for basic research on the nature of cancer. According to recent discoveries, certified cell lines retain most genetic properties of the original tumor and mimic its microenvironment. On the other hand, modern technologies allowing the deepest level of detail in omics landscapes have shown significant differences even between samples of the same cell line due to cross- and mycoplasma infection. This and other observations suggest that, in some cases, cell cultures are not suitable as cancer models, with limited predictive value for the effectiveness of new treatments. HepG2 is a popular hepatic cell line. It is used in a wide range of studies, from the oncogenesis to the cytotoxicity of substances on the liver. In this regard, we set out to collect up-to-date information on the HepG2 cell line to assess whether the level of heterogeneity of the cell line allows in vitro biomedical studies as a model with guaranteed production and quality. Full article

(This article belongs to the Special Issue Liver Cancer)

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13 pages, 472 KiB

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Revisiting Hepatic Artery Infusion Chemotherapy in the Treatment of Advanced Hepatocellular Carcinoma

by Ching-Tso Chen, Tsung-Hao Liu, Yu-Yun Shao, Kao-Lang Liu, Po-Chin Liang and Zhong-Zhe Lin

Int. J. Mol. Sci. 2021, 22(23), 12880; https://doi.org/10.3390/ijms222312880 - 28 Nov 2021

Cited by 18 | Viewed by 5535

Abstract

Hepatic artery infusion chemotherapy (HAIC) is a well-established and common treatment for advanced hepatocellular carcinoma (HCC), particularly in East Asia. However, HAIC is not recognized internationally. Although several trials have demonstrated the safety and efficacy of HAIC, evidence corroborating its overall survival (OS) benefits compared with standard treatments is insufficient. Nevertheless, HAIC may provide prominent benefits in selected patients such as patients with portal vein thrombosis or high intrahepatic tumor burden. Moreover, HAIC has been combined with several therapeutic agents and modalities, including interferon-alpha, multikinase inhibitors, radiation therapy, and immunotherapy, to augment its treatment efficacy. Most of these combinations appeared to increase overall response rates compared with HAIC alone, but results regarding OS are inconclusive. Two prospective randomized controlled trials comparing HAIC plus sorafenib with sorafenib alone have reported conflicting results, necessitating further research. As immunotherapy-based combinations became the mainstream treatments for advanced HCC, HAIC plus immunotherapy-based treatments also showed encouraging preliminary results. The trials of HAIC were heterogeneous in terms of patient selection, chemotherapy regimens and doses, HAIC combination agent selections, and HAIC technical protocols. These heterogeneities may contribute to differences in treatment efficacy, thus increasing the difficulty of interpreting trial results. We propose that future trials of HAIC standardize these key factors to reveal the clinical value of HAIC-based treatments for HCC. Full article

(This article belongs to the Special Issue Liver Cancer)

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