Editorial

3 pages, 172 KiB

Open AccessEditorial

Toward a New Era in the Management of Hepatocellular Carcinoma: Novel Perspectives on Therapeutic Options and Biomarkers

by Daniela Gabbia and Sara De Martin

Int. J. Mol. Sci. 2023, 24(10), 9018; https://doi.org/10.3390/ijms24109018 - 19 May 2023

Cited by 1 | Viewed by 968

Abstract

Liver cancer remains a global health challenge and its incidence is growing worldwide [...] Full article

(This article belongs to the Special Issue Toward a New Era in the Management of Hepatocellular Carcinoma: Novel Perspective on Therapeutic Options and Biomarkers)

Research

Jump to: Editorial, Review

13 pages, 5373 KiB

Open AccessArticle

Effect of Novel AKT Inhibitor Vevorisertib as Single Agent and in Combination with Sorafenib on Hepatocellular Carcinoma in a Cirrhotic Rat Model

by Keerthi Kurma, Ayca Zeybek Kuyucu, Gaël S. Roth, Nathalie Sturm, Marion Mercey-Ressejac, Giovanni Abbadessa, Yi Yu, Herve Lerat, Patrice N. Marche, Thomas Decaens and Zuzana Macek Jilkova

Int. J. Mol. Sci. 2022, 23(24), 16206; https://doi.org/10.3390/ijms232416206 - 19 Dec 2022

Cited by 6 | Viewed by 1779

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The AKT pathway is often activated in HCC cases, and a longer exposure to tyrosine kinase inhibitors such as sorafenib may lead to over-activation of the AKT pathway, leading to [...] Read more.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The AKT pathway is often activated in HCC cases, and a longer exposure to tyrosine kinase inhibitors such as sorafenib may lead to over-activation of the AKT pathway, leading to HCC resistance. Here, we studied the efficacy of a new generation of allosteric AKT inhibitor, vevorisertib, alone or in combination with sorafenib. To identify specific adverse effects related to the background of cirrhosis, we used a diethylnitrosamine (DEN)-induced cirrhotic rat model. Vevorisertib was tested in vitro on Hep3B, HepG2, HuH7 and PLC/PRF cell lines. Rats were treated weekly with intra-peritoneal injections of DEN for 14 weeks to obtain cirrhosis with fully developed HCC. After that, rats were randomized into four groups (n = 7/group): control, sorafenib, vevorisertib and the combination of vevorisertib + sorafenib, and treated for 6 weeks. Tumor progression was followed by MRI. We demonstrated that the vevorisertib is a highly potent treatment, blocking the phosphorylation of AKT. The tumor progression in the rat liver was significantly reduced by treatment with vevorisertib + sorafenib (49.4%) compared to the control group (158.8%, p < 0.0001). Tumor size, tumor number and tumor cell proliferation were significantly reduced in both the vevorisertib group and vevorisertib + sorafenib groups compared to the control group. Sirius red staining showed an improvement in liver fibrosis by vevorisertib and the combination treatment. Moreover, vevorisertib + sorafenib treatment was associated with a normalization in the liver vasculature. Altogether, vevorisertib as a single agent and its combination with sorafenib exerted a strong suppression of tumor progression and improved liver fibrosis. Thus, results provide a rationale for testing vevorisertib in clinical settings and confirm the importance of targeting AKT in HCC. Full article

(This article belongs to the Special Issue Toward a New Era in the Management of Hepatocellular Carcinoma: Novel Perspective on Therapeutic Options and Biomarkers)

► Show Figures

Figure 1

13 pages, 658 KiB

Open AccessArticle

Genetic Variation of SAMM50 Is Not an Independent Risk Factor for Alcoholic Hepatocellular Carcinoma in Caucasian Patients

by Hans Dieter Nischalke, Franziska Schmalz, Stephan Buch, Janett Fischer, Christine Möller, Madlen Matz-Soja, Benjamin Krämer, Bettina Langhans, Alexandra Klüners, Michael Soyka, Felix Stickel, Jacob Nattermann, Thomas Berg, Christian P. Strassburg and Philipp Lutz

Int. J. Mol. Sci. 2022, 23(23), 15353; https://doi.org/10.3390/ijms232315353 - 05 Dec 2022

Cited by 2 | Viewed by 1270

Abstract

Hepatocellular carcinoma (HCC) is a severe complication of advanced alcoholic liver disease, which is modulated by genetic predisposition. Identifying new genetic loci might improve screening. Genetic variation of SAMM50 was linked to HCC. We aimed to validate this finding in a large cohort [...] Read more.

Hepatocellular carcinoma (HCC) is a severe complication of advanced alcoholic liver disease, which is modulated by genetic predisposition. Identifying new genetic loci might improve screening. Genetic variation of SAMM50 was linked to HCC. We aimed to validate this finding in a large cohort of patients with advanced alcoholic liver disease (ALD). A large, well-characterised cohort of patients with alcoholic cirrhosis without (n = 674) and with (n = 386) HCC, as well as controls with HCC due to viral hepatitis (n = 134), controls with heavy alcohol abuse without liver disease (n = 266) and healthy subjects (n = 237), were genotyped for SAMM50 rs3827385 and rs3761472 and for PNPLA3 rs738409. Genotype frequencies were compared between patients with alcohol-associated cirrhosis with and without HCC by uni- and multivariate analysis. Minor variants in both SAMM50 rs3827385 and rs3761472 were significantly more frequent in patients with alcoholic HCC versus alcoholic cirrhosis and versus the control cohorts. An even stronger association was noted for PNPLA3 rs738409. The univariate analysis resulted in an odds ratio (OR) of 1.8 for carriers of at least one minor variant of SAMM50 rs3827385 and rs3761472 (each p < 0.001), but this association was lost in multivariate analysis with age (OR 1.1/year), male sex (OR 3.2), diabetes (OR 1.9) and carriage of PNPLA3 148M (OR 2.1) remaining in the final model. Although minor variants of both SAMM50 loci are strongly associated with alcoholic HCC, this association is not independent of carriage of the well-known risk variant PNPLA3 148M. Full article

(This article belongs to the Special Issue Toward a New Era in the Management of Hepatocellular Carcinoma: Novel Perspective on Therapeutic Options and Biomarkers)

► Show Figures

Figure 1

12 pages, 1834 KiB

Open AccessArticle

iPLA2β-Null Mice Show HCC Protection by an Induction of Cell-Cycle Arrest after Diethylnitrosamine Treatment

by Adriana Andrade, Tanja Poth, Alexander Brobeil, Uta Merle and Walee Chamulitrat

Int. J. Mol. Sci. 2022, 23(22), 13760; https://doi.org/10.3390/ijms232213760 - 09 Nov 2022

Cited by 2 | Viewed by 1494

Abstract

Group VIA phospholipase A2 (iPLA2β) play diverse biological functions in epithelial cells and macrophages. Global deletion in iPLA2β-null (KO) mice leads to protection against hepatic steatosis in non-alcoholic fatty liver disease, in part, due to the replenishment of the loss of hepatocellular phospholipids. [...] Read more.

Group VIA phospholipase A2 (iPLA2β) play diverse biological functions in epithelial cells and macrophages. Global deletion in iPLA2β-null (KO) mice leads to protection against hepatic steatosis in non-alcoholic fatty liver disease, in part, due to the replenishment of the loss of hepatocellular phospholipids. As the loss of phospholipids also occurs in hepatocellular carcinoma (HCC), we hypothesized that global deletion in KO mice may lead to protection against HCC. Here, HCC induced by diethylnitrosamine (DEN) was chosen because DEN causes direct injury to the hepatocytes. Male wild-type (WT) and KO mice at 3–5 weeks of age (12–13 mice/group) were subjected to a single intraperitoneal treatment with 10 mg/kg DEN, and mice were killed 12 months later. Analyses of histology, plasma cytokines, and gene expression were performed. Due to the low-dose DEN used, we observed a liver nodule in 3 of 13 WT and 2 of 12 KO mice. Only one DEN-treated WT mouse was confirmed to have HCC. DEN-treated KO mice did not show any HCC but showed suppressed hepatic expression of cell-cycle cyclinD2 and BCL2 as well as inflammatory markers IL-1β, IL-10, and VCAM-1. Notably, DEN-treated KO mice showed increased hepatic necrosis and elevated levels of plasma lactate dehydrogenase suggesting an exacerbation of liver injury. Thus, global iPLA2β deficiency in DEN-treated mice rendered HCC protection by an induction of cell-cycle arrest. Our results suggest the role of iPLA2β inhibition in HCC treatment. Full article

(This article belongs to the Special Issue Toward a New Era in the Management of Hepatocellular Carcinoma: Novel Perspective on Therapeutic Options and Biomarkers)

► Show Figures

Figure 1

19 pages, 5480 KiB

Open AccessArticle

Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells

by Manabu Okumura, Tomomi Iwakiri, Naoki Yoshikawa, Takao Nagatomo, Takanori Ayabe, Isao Tsuneyoshi and Ryuji Ikeda

Int. J. Mol. Sci. 2022, 23(16), 9108; https://doi.org/10.3390/ijms23169108 - 14 Aug 2022

Cited by 2 | Viewed by 1597

Abstract

Aberrant activation of hepatocyte growth factor (HGF) and its receptor c-Met axis promotes tumor growth. Therefore, many clinical trials have been conducted. A phase 3 trial investigating a monoclonal antibody targeting HGF in combination with fluoropyrimidine-based chemotherapy had to be terminated prematurely; however, [...] Read more.

Aberrant activation of hepatocyte growth factor (HGF) and its receptor c-Met axis promotes tumor growth. Therefore, many clinical trials have been conducted. A phase 3 trial investigating a monoclonal antibody targeting HGF in combination with fluoropyrimidine-based chemotherapy had to be terminated prematurely; however, the reason behind the failure remains poorly defined. In this study, we investigated the influence of HGF on the antineoplastic effects of 5-fluorouracil (5-FU), a fluoropyrimidine, in HepG2 cells. HGF suppressed the proliferative activity of cells concomitantly treated with 5-FU more robustly as compared to that of cells treated with 5-FU alone, and markedly increased the expression of uridine phosphorylase 1 (UPP1). Intracellular concentration of 5-fluorouridine, an initial anabolite of 5-FU catalyzed by UPP1, was increased by HGF. Interestingly, erlotinib enhanced HGF-induced increase in UPP1 mRNA; in contrast, gefitinib suppressed it. Furthermore, erlotinib suppressed HGF-increased phosphorylation of the epidermal growth factor receptor at the Tyr1173 site involved in downregulation of extracellular signal-regulated kinase (Erk) activation, and enhanced the HGF-increased phosphorylation of Erk. Collectively, these findings suggest that inhibition of the HGF/c-Met axis diminishes the effects of fluoropyrimidine through downregulation of UPP1 expression. Therefore, extreme caution must be exercised in terms of patient safety while offering chemotherapy comprising fluoropyrimidine concomitantly with inhibitors of the HGF/c-Met axis. Full article

(This article belongs to the Special Issue Toward a New Era in the Management of Hepatocellular Carcinoma: Novel Perspective on Therapeutic Options and Biomarkers)

► Show Figures

Graphical abstract

17 pages, 1868 KiB

Open AccessArticle

Expression of Cellular and Extracellular TERRA, TERC and TERT in Hepatocellular Carcinoma

by Michele Manganelli, Ilaria Grossi, Jessica Corsi, Vito Giuseppe D’Agostino, Katarina Jurikova, Emilio Cusanelli, Sarah Molfino, Nazario Portolani, Alessandro Salvi and Giuseppina De Petro

Int. J. Mol. Sci. 2022, 23(11), 6183; https://doi.org/10.3390/ijms23116183 - 31 May 2022

Cited by 15 | Viewed by 2590

Abstract

Non-coding RNAs are transcribed from telomeres and the telomeric repeat-containing RNAs (TERRA) are implicated in telomere homeostasis and in cancer. In this study, we aimed to assess in hepatocellular carcinoma (HCC) the cellular and extracellular expression of TERRA, the telomerase [...] Read more.

Non-coding RNAs are transcribed from telomeres and the telomeric repeat-containing RNAs (TERRA) are implicated in telomere homeostasis and in cancer. In this study, we aimed to assess in hepatocellular carcinoma (HCC) the cellular and extracellular expression of TERRA, the telomerase RNA subunit (TERC) and the telomerase catalytic subunit (TERT). We determined by qPCR the expression level of TERRA 1_2_10_13q, TERRA 15q, TERRA XpYp, TERC and of TERT mRNA in HCC tissues and in the plasma of HCC patients. Further, we profiled the same transcripts in the HCC cell lines, HA22T/VGH and SKHep1C3, and in the extracellular vesicles (EVs) derived from their secretomes. We found that the expression of TERRA and TERT mRNA was significantly deregulated in HCC, being TERRA downregulated and TERT mRNA upregulated in HCC tissues vs. the peritumoral (PT) ones, and the receiver operating characteristic (ROC) curve analyses revealed a significant ability in discriminating HCC from PT tissue. Further, the determinations of circulating TERRA and TERC showed higher amounts of these transcripts in the plasma of HCC patients vs. controls and ROC analyses gave significant results. The expression characterization of the cultured HCC cells showed their ability to produce and secrete TERRA and TERC into the EVs; the ability to produce TERT mRNA that was not detectable in the EVs; and the ability to respond to sorafenib treatment increasing TERRA expression. Our results highlight that: (i) both cellular and extracellular expressions of TERRA and TERC are dysregulated in HCC as well as the cellular expression of TERT mRNA and (ii) the combined detection of TERRA and TERC in plasma may represent a promising approach for non-invasive diagnostic molecular indicators of HCC. Full article

(This article belongs to the Special Issue Toward a New Era in the Management of Hepatocellular Carcinoma: Novel Perspective on Therapeutic Options and Biomarkers)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

20 pages, 2840 KiB

Open AccessReview

Translational Control of Metabolism and Cell Cycle Progression in Hepatocellular Carcinoma

by Alessandra Scagliola, Annarita Miluzio and Stefano Biffo

Int. J. Mol. Sci. 2023, 24(5), 4885; https://doi.org/10.3390/ijms24054885 - 03 Mar 2023

Cited by 5 | Viewed by 2293

Abstract

The liver is a metabolic hub characterized by high levels of protein synthesis. Eukaryotic initiation factors, eIFs, control the first phase of translation, initiation. Initiation factors are essential for tumor progression and, since they regulate the translation of specific mRNAs downstream of oncogenic [...] Read more.

The liver is a metabolic hub characterized by high levels of protein synthesis. Eukaryotic initiation factors, eIFs, control the first phase of translation, initiation. Initiation factors are essential for tumor progression and, since they regulate the translation of specific mRNAs downstream of oncogenic signaling cascades, may be druggable. In this review, we address the issue of whether the massive translational machinery of liver cells contributes to liver pathology and to the progression of hepatocellular carcinoma (HCC); it represents a valuable biomarker and druggable target. First, we observe that the common markers of HCC cells, such as phosphorylated ribosomal protein S6, belong to the ribosomal and translational apparatus. This fact is in agreement with observations that demonstrate a huge amplification of the ribosomal machinery during the progression to HCC. Some translation factors, such as eIF4E and eIF6, are then harnessed by oncogenic signaling. In particular, the action of eIF4E and eIF6 is particularly important in HCC when driven by fatty liver pathologies. Indeed, both eIF4E and eIF6 amplify at the translational level the production and accumulation of fatty acids. As it is evident that abnormal levels of these factors drive cancer, we discuss their therapeutic value. Full article

(This article belongs to the Special Issue Toward a New Era in the Management of Hepatocellular Carcinoma: Novel Perspective on Therapeutic Options and Biomarkers)

► Show Figures

Figure 1

23 pages, 1144 KiB

Open AccessReview

Tumor Mutational Burden for Predicting Prognosis and Therapy Outcome of Hepatocellular Carcinoma

by Daniela Gabbia and Sara De Martin

Int. J. Mol. Sci. 2023, 24(4), 3441; https://doi.org/10.3390/ijms24043441 - 08 Feb 2023

Cited by 12 | Viewed by 2723

Abstract

Hepatocellular carcinoma (HCC), the primary hepatic malignancy, represents the second-highest cause of cancer-related death worldwide. Many efforts have been devoted to finding novel biomarkers for predicting both patients’ survival and the outcome of pharmacological treatments, with a particular focus on immunotherapy. In this [...] Read more.

Hepatocellular carcinoma (HCC), the primary hepatic malignancy, represents the second-highest cause of cancer-related death worldwide. Many efforts have been devoted to finding novel biomarkers for predicting both patients’ survival and the outcome of pharmacological treatments, with a particular focus on immunotherapy. In this regard, recent studies have focused on unravelling the role of tumor mutational burden (TMB), i.e., the total number of mutations per coding area of a tumor genome, to ascertain whether it can be considered a reliable biomarker to be used either for the stratification of HCC patients in subgroups with different responsiveness to immunotherapy, or for the prediction of disease progression, particularly in relation to the different HCC etiologies. In this review, we summarize the recent advances on the study of TMB and TMB-related biomarkers in the HCC landscape, focusing on their feasibility as guides for therapy decisions and/or predictors of clinical outcome. Full article

(This article belongs to the Special Issue Toward a New Era in the Management of Hepatocellular Carcinoma: Novel Perspective on Therapeutic Options and Biomarkers)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Toward a New Era in the Management of Hepatocellular Carcinoma: Novel Perspective on Therapeutic Options and Biomarkers

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (8 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI