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Liver hepatocellular carcinoma (LIHC) is among the most lethal human cancers. Studies have shown that Homer scaffold protein 3 (HOMER3) plays important roles in various diseases and cancers, but its biological function and molecular mechanism in LIHC have never been investigated. Our study discovered the aberrantly high expression of HOMER3 and its promising diagnostic and prognostic significance in LIHC. Functionally, HOMER3 knockdown inhibited the proliferative and migrative abilities of LIHC cells and tumor growth in vivo. Mechanically, HOMER3 mediated the aggressiveness of LIHC cells via GPNMB. Meanwhile, miR-361 directly targeted GPNMB and attenuated LIHC progression by suppressing GPNMB expression. The regulatory effect of HOMER3 during LIHC progression was exerted through the miR-361/GPNMB axis. Furthermore, EZH2 supplementation or miR-361 depletion effectively abated the tumor-suppressive effect of HOMER3 knockdown on LIHC progression. In conclusion, HOMER3 mediated LIHC progression through the EZH2/miR-361/GPNMB axis., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

SIAH2 function as an oncogene in various cancer. However, the roles of SIAH2 in hepatocellular carcinoma (HCC) are still unknown. This study aimed to investigate the roles of SIAH2 in HCC. Immunohistochemistry was used determine SIAH2 and ACSL4 expression in clinical samples. RT-qPCR was used to determine mRNA expression. Western blot assay was applied for determining protein expression. Ubiquitination assay was conducted for determining ubiquitination of ACSL4. Xenograft experiment was applied for determining tumor growth. Flow cytometry was applied to determine the functions of CD4+ and CD8+ T cells. SIAH2 expression was overexpressed in HCC tumors. High levels of SIAH2 predicted poor outcomes. However, SIAH2 knockdown promoted the proliferation of CD8+ T cells as well as promoted the ferroptosis of tumor cells, inhibiting tumor growth in HCC. ACSL4 is required for CD8+ T cell-mediated ferroptosis of HCC cells. However, SIAH2 induced ubiquitination of ACSL4 and inhibited its expression. SIAH2 specific inhibitor menadione promoted the immune checkpoint blockade. Taken together, SIAH2-mediated inactivation of CD8+ T cells inhibits the ferroptosis of HCC via mediating ubiquitination of ACSL4. Therefore, targeting SIAH2 may be a promising strategy for HCC.

Objective: This study mainly explores how UCK2 impacts the progression of hepatocellular carcinoma (HCC). Methods: Mature miRNA and mRNA expression data along with the clinical data of HCC were provided by The Cancer Genome Atlas to mine differentially expressed miRNAs and mRNAs. Expression levels of UCK2 and miR-139-3p in HCC were tested through quantitative real-time PCR. How UCK2 and miR-139-3p impacted HCC cell activities were detected by Transwell, wound healing and cell proliferation approaches. Whether miR-139-3p could bind to UCK2 was detected by dual-luciferase assay. Results: This investigation found evidently high levels of UCK2 in both HCC tissue and cells and its marked association with poor prognosis. Overexpression of UCK2 could significantly promote the behaviors of HCC cells. In addition, poorly expressed miR-139-3p was inversely associated with UCK2 . Dual-luciferase method also proved the association. The rescue experiment showed that miR-139-3p regulated cell behaviors in HCC through targeting UCK2 . Conclusion: Highly expressed UCK2 was mediated by miR-139-3p to modulate cell behaviors in HCC. It is assumed that UCK2 is a possible target of HCC for cancer therapy purposes.

Introduction and Objectives: Hepatocellular carcinoma (HCC) is one of the most common and fatal cancers in the world. This study aims to investigate the mechanism by which miR-221-3p regulates HCC cell proliferation, migration and invasion, so as to provide a new idea for targeted therapy towards HCC., Materials and Methods: Expression quantification data including mature miRNA and mRNA were accessed from TCGA-LIHC dataset, and matched clinical information was obtained as well, which helped identify the miRNA of interest. Thereafter, effect of the miRNA on HCC cell biological functions was assessed with a series of in vitro experiments, such as qRT-PCR, MTT, wound healing assay and Transwell. To gain more insight into the mechanism of the miRNA in HCC, bioinformatics method was conducted to predict downstream target gene. The potential targeting relationship between the miRNA and the predicted mRNA was validated by dual-luciferase reporter assay. Western blot was performed to test protein expression., Results: MiR-221-3p identified by differential expression analysis was found to be significantly elevated in HCC tissue. Overexpressing miR-221-3p noticeably enhanced HCC cell proliferative, migratory and invasive abilities. Leukemia inhibitory factor receptor (LIFR), confirmed as a downstream target of miR-221-3p in HCC by dual-luciferase reporter assay, was poorly expressed in HCC tissue and cells. Additionally, the expression of LIFR was decreased following the targeted binding between miR-221-3p and LIFR 3'-UTR, while increasing the expression of LIFR attenuated the promoting effect of miR-221-3p on HCC cells., Conclusion: MiR-221-3p is an oncogene in HCC cells, and it exerts its role in HCC cell viability and motility via targeting LIFR., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2021 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

The zinc finger protein Snail1 is an important factor in the regulation of the epithelial‑mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) cells. The present study demonstrated that the expression of Snail1 in HCC tissues was significantly higher compared with its expression in tissues adjacent to primary sites, as determined via western blotting. Furthermore, the results of a dual luciferase assay revealed that hsa‑microRNA(miR)199a‑5p negatively regulated the protein expression of Snail1 by binding to its 3' untranslated region. However, in a comparative analysis of primary HCC and its metastatic tissues using reverse transcription‑quantitative polymerase chain reaction and western blotting, it was demonstrated that the expression of hsa‑miR199a‑5p and Snail1 in HCC metastatic tissues were significantly higher compared with primary lesions and an association between them identified that hsa‑miR199a‑5p lost its ability to negatively regulate Snail1. This result is contradictive to the fact that hsa‑miR199a‑5p inhibits the expression of the Snail1 protein. The present study hypothesized that the aberrant expression of long non‑coding RNA was the cause of hsa‑miR199a‑5p inactivation based on loss of function rather than a reduction in content. The data collected in the present study confirmed the hypothesis that AB209371 binds to hsa‑miR199a‑5p and weakened the inhibitory effect of hsa‑miR199a‑5p on Snail1 expression. In addition, an in vitro EMT model was established in the present study by inducing HCC cells with TGF‑β1. The results revealed that AB209371 silencing effectively reversed the hsa‑miR199a‑5p mediated inhibition of EMT by negatively regulating Snail1 protein expression. Therefore, AB209371 silencing in combination with hsa‑miR199a‑5p expression may serve as an effective means to inhibit EMT in HCC cells. The present study also revealed that hsa‑miR199a‑5p/Snail1 exhibits a dominant regulatory effect in the EMT of HCC cells via a Snail1 recovery experiment. In conclusion, to the best of our knowledge, the present study confirmed for the first time that the high expression of AB209371 is favorable for the EMT in HCC cells and may be a direct cause of hsa‑miR199a‑5p inactivation (an HCC metastasis suppressor). Additionally, AB209371 silencing combined with hsa‑miR199a‑5p overexpression may be an effective means to inhibit the metastasis of HCC and the EMT of HCC cells.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer‑related mortality worldwide. An increasing number of studies have demonstrated that microRNAs may be used as diagnostic, therapeutic and prognostic targets for human cancers, including HCC. The present study aimed to evaluate microRNA (miR)‑302a expression and function in HCC, and its underlying mechanisms. The results revealed that miR‑302a was expressed at low levels in HCC tissues and cell lines. Reduced miR‑302a expression was correlated with tumor‑node‑metastasis stage and lymph node metastasis in patients with HCC. Additionally, overexpression of miR‑302a reduced cell proliferation and invasion, and induced apoptosis in HCC cells. Vascular endothelial growth factor A (VEGFA) was demonstrated to be a direct target gene of miR‑302a. VEGFA was highly expressed in HCC tissues and inversely correlated with miR‑302a expression. Knockdown of VEGFA expression led to reduced HCC cell proliferation and invasion, and increased apoptosis rates, similar to miR‑302a overexpression, which suggested that VEGFA may be a functional downstream target of miR‑302a in HCC. These data suggested that this newly identified miR‑302a/VEGFA axis may be involved in HCC formation and progression. The present results also provide novel potential targets for the treatments of patients with HCC.

Hepatocellular carcinoma is one of the most common and lethal cancers worldwide, especially in developing countries. In the present study, we found that the expression of a microRNA, miR-590-5P, was down-regulated and S100A10 was up-regulated in six hepatocellular carcinoma cell lines. The reporter gene assay showed that overexpression of miR-590-5P effectively reduced the activity of luciferase expressed by a vector bearing the 3' untranslated region of S100A10 mRNA. Ectopic miR-590-5P overexpression mediated by lentiviral infection decreased expression of S100A10. Infection of Lv-miR-590-5P inhibited cell growth and induced cell cycle G1 arrest in HepG2 cells. In addition, miR-590-5P expression suppressed the expression of Wnt5a, cMyc and cyclin D1, and increased the phosphorylation of β-catenin and expression of Caspase 3, which may contribute to the inhibitory effect of miR-590-5P on cell growth. Taken together, our data suggest that down-regulation of miR-590-5P is involved in hepatocellular carcinoma and the restoration of miR-590-5P can impair the growth of cancer cells, suggesting that miR-590-5P may be a potential target molecule for the therapy of hepatocellular carcinoma.