MiR-182-5p Is Upregulated in Hepatic Tissues from a Diet-Induced NAFLD/NASH/HCC C57BL/6J Mouse Model and Modulates Cyld and Foxo1 Expression

Abstract

Non-alcoholic fatty liver disease (NAFLD) is considered a relevant liver chronic disease. Variable percentages of NAFLD cases progress from steatosis to steatohepatitis (NASH), cirrhosis and, eventually, hepatocellular carcinoma (HCC). In this study, we aimed to deepen our understanding of expression levels and functional relationships between miR-182-5p and Cyld-Foxo1 in hepatic tissues from C57BL/6J mouse models of diet-induced NAFL/NASH/HCC progression. A miR-182-5p increase was detected early in livers as NAFLD damage progressed, and in tumors compared to peritumor normal tissues. An in vitro assay on HepG2 cells confirmed Cyld and Foxo1, both tumor-suppressor, as miR-182-5p target genes. According to miR-182-5p expression, decreased protein levels were observed in tumors compared to peritumor tissues. Analysis of miR-182-5p, Cyld and Foxo1 expression levels, based on datasets from human HCC samples, showed results consistent with those from our mouse models, and also highlighted the ability of miR-182-5p to distinguish between normal and tumor tissues (AUC 0.83). Overall, this study shows, for the first time, miR-182-5p overexpression and Cyld-Foxo1 downregulation in hepatic tissues and tumors from a diet-induced NAFLD/HCC mouse model. These data were confirmed by the analysis of datasets from human HCC samples, highlighting miR-182-5p diagnostic accuracy and demonstrating the need for further studies to assess its potential role as a biomarker or therapeutic target.

Serum microRNA Profiles and Pathways in Hepatitis B-Associated Hepatocellular Carcinoma: A South African Study

“…Conversely, upregulated miR-483-5p inhibits cell proliferation and fibrosis by targeting PPARα and TIMP2 [34]. Other miRNAs in our results that might modulate cell proliferation in HBV-HCC include miR-874-3p [141], miR-451a [142][143][144][145][146][147], miR-182-5p [148][149][150][151][152][153], miR-98-5p [154][155][156][157][158], miR-363-3p [159][160][161][162] and miR-339-3p [163][164][165].…”

Impaired Physiological Regulation of ß Cells: Recent Findings from Type 2 Diabetic Patients

“…Cultured human islets have increased levels of miRNA-146 in response to pro-inflammatory cytokines exposure decreased levels after high glucose exposure and interestingly stable levels after palmitate exposure [164]. Apart from the regulation of inflammatory response, miRNA-146 and miRNA 182-5p have also been involved in the reduction of cytoplasmic accumulation of lipids and cellular inflammatory response [165,166]. β-cell lines exposed to stearic acid and palmitic acid exhibit reduced expression of miRNA-297b-5p whereas the increased miRNA-297b-5p levels help to minimize apoptosis induced by stearic acid but also result in reduced insulin concentration [161].…”

Crosstalk between Epigenetics and Metabolic Reprogramming in Metabolic Dysfunction-Associated Steatotic Liver Disease-Induced Hepatocellular Carcinoma: A New Sight

“…Likewise, research conducted by Rodrigues et al revealed that miR-21 acts as a crucial instigator of the whole-spectrum MASLD advancement and assumes an equally significant part in the evolution of MASLD to HCC [ 52 ]. It is worth mentioning that several miRNAs are differentially expressed in the transitions from MASLD to MASH to HCC, with some being overexpressed in tumors (miR-155, miR-193b, miR-182) while others are downregulated in HCC (miR-20a, miR-200c, miR-483) [ 53 , 54 , 55 ].…”