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Chronic Liver Disease and Hepatocellular Carcinoma

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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: 30 June 2024 | Viewed by 3607

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Dr. Daniela Gabbia

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Department of Pharmaceutical and Pharmacological Sciences, University of Padova, L.go Meneghetti 2, 35131 Padova, Italy
Interests: chronic liver disease; hepatocellular carcinoma; liver metabolism
Special Issues, Collections and Topics in MDPI journals

Dr. Sara Carpi

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1. Department of Health Sciences, University ‘Magna Græcia’ of Catanzaro, Viale Europa, Località Germaneto, 88100 Catanzaro, Italy
2. NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy
Interests: pharmacology; molecular pharmacology; microRNA
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chronic liver disease of different aetiologies, such as viral, metabolic-derived, or autoimmune pathologies, represents a major risk factor for the development of hepatocellular carcinoma (HCC). This primary liver malignancy has been the sixth most diagnosed cancer in 2020, and the third leading cause of cancer-related death worldwide. Due to high morbidity and mortality, as well as growing incidence, HCC represents a global health challenge. Since about 80% of patients develop HCC as consequence of chronic liver disease and cirrhosis, many studies are focusing on unravelling the molecular mechanisms responsible for its development and progression in order to find new therapeutic targets and predictive marker of its prognosis that could prevent the progression of chronic disease to cancer. Studies that focus on this topic are welcome in this Special Issue.

This Special Issue aims to provide new insights on novel molecular targets, therapeutic options, and/or biomarkers which could be helpful in preventing the progression of chronic liver disease to HCC and that could potentially be exploited in clinical development. Studies investigating naturally derived materials are also welcome, even though they must report a precise description of the active ingredients of the plant extract.

Dr. Daniela Gabbia
Dr. Sara Carpi
Guest Editors

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Keywords

hepatocellular carcinoma
NAFLD/NASH
viral hepatitis
autoimmune liver disease
immunotherapy
biomarker

Published Papers (4 papers)

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Research

13 pages, 1540 KiB

Open AccessArticle

ADAMTS-13: A Prognostic Biomarker for Portal Vein Thrombosis in Japanese Patients with Liver Cirrhosis

by Junya Suzuki, Tadashi Namisaki, Hiroaki Takya, Kosuke Kaji, Norihisa Nishimura, Akihiko Shibamoto, Shohei Asada, Takahiro Kubo, Satoshi Iwai, Fumimasa Tomooka, Soichi Takeda, Aritoshi Koizumi, Misako Tanaka, Takuya Matsuda, Takashi Inoue, Yuki Fujimoto, Yuki Tsuji, Yukihisa Fujinaga, Shinya Sato, Koh Kitagawa, Hideto Kawaratani, Takemi Akahane, Akira Mitoro, Masanori Matsumoto, Kiyoshi Asada and Hitoshi Yoshiji Show full author list Hide full author list

Int. J. Mol. Sci. 2024, 25(5), 2678; https://doi.org/10.3390/ijms25052678 - 26 Feb 2024

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Abstract

Portal vein thrombosis (PVT), one of the most prevalent hepatic vascular conditions in patients with liver cirrhosis (LC), is associated with high mortality rates. An imbalance between a disintegrin-like metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS-13) enzyme and von Willebrand factor (VWF) is responsible for hypercoagulability, including spontaneous thrombus formation in blood vessels. Herein, we aimed to identify potential prognostic and diagnostic biomarkers in Japanese patients with LC and PVT. In total, 345 patients were divided into two groups: 40 patients who developed PVT (PVT group) and 305 who did not develop PVT (NPVT group). Among the 345 patients with LC, 81% (279/345) were deemed ineligible due to the presence of preventive comorbidities, active or recent malignancies, and organ dysfunction. The remaining 66 patients were divided into two groups: the PVT group (n = 33) and the NPVT group (n = 33). Plasma ADAMTS-13 activity (ADAMTS-13:AC) and the vWF antigen (VWF:Ag) were measured using enzyme-linked immunosorbent assays. Contrast-enhanced, three-dimensional helical computed tomography (CT) was used to detect and characterize PVT. ADAMTS-13:AC was significantly lower in the PVT group than in the NPVT group. No significant differences in plasma vWF:Ag or liver stiffness were observed between the two groups. ADAMTS-13:AC of <18.8 was an independent risk factor for PVT on multivariate analyses (odds ratio: 1.67, 95% confidence interval: 1.21–3.00, p < 0.002). The receiver operating characteristic analysis of ADAMTS-13:AC revealed an area under the curve of 0.913 in PVT detection. Patients with PVT having ADAMTS-13:AC ≥18.8 (n = 17) had higher albumin levels and better prognoses than those with ADAMTS-13:AC <18.8 (n = 16). No significant correlations of ADAMTS-13:AC levels with either fibrin degradation product or D-dimer levels were observed. ADAMTS-13:AC levels could be potential diagnostic and prognostic biomarkers for PVT in Japanese patients with LC. Full article

(This article belongs to the Special Issue Chronic Liver Disease and Hepatocellular Carcinoma)

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16 pages, 689 KiB

Open AccessArticle

MicroRNAs as Plasma Biomarkers of Hepatocellular Carcinoma in Patients with Liver Cirrhosis—A Cross-Sectional Study

by Robin Zenlander, Hugh Salter, Stefan Gilg, Gösta Eggertsen and Per Stål

Int. J. Mol. Sci. 2024, 25(4), 2414; https://doi.org/10.3390/ijms25042414 - 19 Feb 2024

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Abstract

Ultrasound screening for hepatocellular carcinoma (HCC) in patients with liver cirrhosis has a poor sensitivity for small tumors. Circulating microRNAs (miRNAs) have been explored as HCC biomarkers, but results are diverging. Here, we evaluate if miRNAs up-regulated in HCC tissue can be detected in plasma and used as screening biomarkers for HCC. In this cross-sectional study, plasma, HCC tissue and surrounding non-tumorous liver tissue were collected from liver resections. Tissue miRNAs were identified and quantitated by RNA-sequencing analysis, and the fold-changes between HCC and surrounding liver tissue were calculated. The miRNAs up-regulated in HCCs were then re-analyzed in plasma from the same patients, and the miRNAs with the highest plasma levels were subsequently measured in plasma from an independent cohort of patients with cirrhosis or HCC. In tissues from 84 resected patients, RNA-sequencing detected 197 differentially expressed miRNAs, 40 of which had a raw count above 200 and were analyzed in plasma from the same cohort. Thirty-one miRNAs were selected for further analysis in 200 patients with HCC or cirrhosis. Of these, eleven miRNAs were significantly increased in HCC as compared to cirrhosis patients. Only miR-93-5p and miR-151a-3p were significantly associated with HCC, with an AUC of 0.662. In comparison, alpha-fetoprotein and des-gamma-carboxy prothrombin yielded an AUC of 0.816, which increased to 0.832 if miR-93-5p and miR-151a-3p were added. When including sex and age, the addition of miR-93-5p and miR-151a-3p did not further improve the AUC (from 0.910 to 0.911). In conclusion, micro-RNAs up-regulated in HCCs are detectable in plasma but have a poor performance as screening biomarkers of HCC. Full article

(This article belongs to the Special Issue Chronic Liver Disease and Hepatocellular Carcinoma)

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24 pages, 6363 KiB

Open AccessArticle

Vinorelbine Improves the Efficacy of Sorafenib against Hepatocellular Carcinoma: A Promising Therapeutic Approach

by Wai Har Ng, Khee Chee Soo and Hung Huynh

Int. J. Mol. Sci. 2024, 25(3), 1563; https://doi.org/10.3390/ijms25031563 - 26 Jan 2024

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Abstract

Hepatocellular carcinoma (HCC) is a leading global cause of cancer-related mortality. Despite the widespread adoption of sorafenib as the standard HCC treatment, its efficacy is constrained, frequently encountering resistance. To augment the effectiveness of sorafenib, this study investigated the synergy of sorafenib and vinorelbine using 22 HCC patient-derived xenograft (PDX) models. In this study, mice bearing HCC tumors were treated with the vehicle, sorafenib (15 mg/kg), vinorelbine (3 mg/kg), and sorafenib–vinorelbine combination (Sora/Vino). Rigorous monitoring of the tumor growth and side effects coupled with comprehensive histological and molecular analyses was conducted. The overall survival (OS) of mice bearing HCC orthotopic tumors was also assessed. Our data showed a notable 86.4% response rate to Sora/Vino, surpassing rates of 31.8% for sorafenib and 9.1% for vinorelbine monotherapies. Sora/Vino significantly inhibited tumor growth, prolonged OS of mice bearing HCC orthotopic tumors (p < 0.01), attenuated tumor cell proliferation and angiogenesis, and enhanced necrosis and apoptosis. The combination therapy effectively suppressed the focal adhesion kinase (FAK) pathway, which is a pivotal player in cell proliferation, tumor angiogenesis, survival, and metastasis. The noteworthy antitumor activity in 22 HCC PDX models positions Sora/Vino as a promising candidate for early-phase clinical trials, leveraging the established use of sorafenib and vinorelbine in HCC and other cancers. Full article

(This article belongs to the Special Issue Chronic Liver Disease and Hepatocellular Carcinoma)

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20 pages, 28176 KiB

Open AccessArticle

BMP9-ID1 Pathway Attenuates N⁶-Methyladenosine Levels of CyclinD1 to Promote Cell Proliferation in Hepatocellular Carcinoma

by Han Chen, Mingming Zhang, Jianhao Li, Miao Liu, Dan Cao, Ying-Yi Li, Taro Yamashita, Kouki Nio and Hong Tang

Int. J. Mol. Sci. 2024, 25(2), 981; https://doi.org/10.3390/ijms25020981 - 12 Jan 2024

Viewed by 791

Abstract

Hepatocellular carcinoma (HCC) is a highly lethal malignant neoplasm, and the involvement of bone morphogenetic protein 9 (BMP9) has been implicated in the pathogenesis of liver diseases and HCC. Our goal was to investigate the role of BMP9 signaling in regulating N6-methyladenosine (m⁶A) methylation and cell cycle progression, and evaluate the therapeutic potential of BMP receptor inhibitors for HCC treatment. We observed that elevated levels of BMP9 expression in tumor tissues or serum samples from HCC patients were associated with a poorer prognosis. Through in vitro experiments utilizing the m⁶A dot blotting assay, we ascertained that BMP9 reduced the global RNA m⁶A methylation level in Huh7 and Hep3B cells, thereby facilitating their cell cycle progression. This effect was mediated by an increase in the expression of the inhibitor of DNA-binding protein 1 (ID1). Additionally, using methylated RNA immunoprecipitation qPCR(MeRIP-qPCR), we showed that the BMP9-ID1 pathway promoted CyclinD1 expression by decreasing the m⁶A methylation level in the 5′ UTR of mRNA. This occurred through the upregulation of the fat mass and obesity-associated protein (FTO) in Huh7 and Hep3B cells. In our in vivo mouse xenograft models, we demonstrated that blocking the BMP receptor with LDN-212854 effectively suppressed HCC growth and induced global RNA m⁶A methylation. Overall, our findings indicate that the BMP9-ID1 pathway promotes HCC cell proliferation by down-regulating the m⁶A methylation level in the 5′ UTR of CyclinD1 mRNA. Targeting the BMP9-ID1 pathway holds promise as a potential therapeutic strategy for treating HCC. Full article

(This article belongs to the Special Issue Chronic Liver Disease and Hepatocellular Carcinoma)

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