MicroRNA-483-5p Inhibits Hepatocellular Carcinoma Cell Proliferation, Cell Steatosis, and Fibrosis by Targeting PPARα and TIMP2

Abstract

MicroRNAs (miRNAs) are small non-coding RNA molecules that bind with the 3′ untranslated regions (UTRs) of genes to regulate expression. Downregulation of miR-483-5p (miR-483) is associated with the progression of hepatocellular carcinoma (HCC). However, the significant roles of miR-483 in nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver diseases (AFLD), and HCC remain elusive. In the current study, we investigated the biological significance of miR-483 in NAFLD, AFLD, and HCC in vitro and in vivo. The downregulation of miR-483 expression in HCC patients’ tumor samples was associated with Notch 3 upregulation. Overexpression of miR-483 in a human bipotent progenitor liver cell line HepaRG and HCC cells dysregulated Notch signaling, inhibited cell proliferation/migration, induced apoptosis, and increased sensitivity towards antineoplastic agents sorafenib/regorafenib. Interestingly, the inactivation of miR-483 upregulated cell steatosis and fibrosis signaling by modulation of lipogenic and fibrosis gene expression. Mechanistically, miR-483 targets PPARα and TIMP2 gene expression, which leads to the suppression of cell steatosis and fibrosis. The downregulation of miR-483 was observed in mice liver fed with a high-fat diet (HFD) or a standard Lieber-Decarli liquid diet containing 5% alcohol, leading to increased hepatic steatosis/fibrosis. Our data suggest that miR-483 inhibits cell steatosis and fibrogenic signaling and functions as a tumor suppressor in HCC. Therefore, miR-483 may be a novel therapeutic target for NAFLD/AFLD/HCC management in patients with fatty liver diseases and HCC.

miR-483-5p orchestrates the initiation of protein synthesis by facilitating the decrease in phosphorylated Ser209eIF4E and 4E-BP1 levels

“…5 b. In certain cell lines miR-483-5p promoted 46 , 49 whereas in other cell lines it inhibited the proliferation, invasion and metastasis 29 , 47 , 50 . One possible mechanism for such divergent phenotypes could be due to the net outcome of the collective miRNA-mRNA interactions, probably stemming from the differences in available mRNA targets and their competition for miR-483-5p binding (Fig.…”

“…In physiological contexts, miR-483-5p plays a role in preserving the function and identity of pancreatic β-cells, promoting adipogenesis in adipose tissue, and alleviating hyperlipidemia-associated fatty liver disease 45 . Dysregulation of miR-483-5p is associated with various diseases, including cancer 46 , 47 , type 2 diabetes, fatty liver disease, diabetic nephropathy, and neurological injury 45 . Recognizing that miR-483-5p regulates the ERK1/MKNK1 axis could be a crucial information for modulating both physiological and pathological conditions.…”

Impacts of MicroRNA-483 on Human Diseases

“…Overexpression of miR-483 inhibits mouse liver fibrosis by targeting tissue inhibitor of metalloproteinase 2 ( TIMP2 ) and platelet-derived growth factor-β ( PDGF-β ). A recent report indicates that miR-483-5p expression is lower in NAFLD and AFLD mouse models and human hepatocellular carcinoma (HCC) tissue samples [ 39 ]. The downregulation of miR-483-5p increases not only TIMP2 expression but also peroxisome proliferator-activated receptor alpha ( PPARα ) and transforming growth factor beta ( TGF-β ) expression ( Table 1 , Figure 2 ).…”

Roles of peroxisome proliferator‐activated receptors in hepatocellular carcinoma

“…In addition, 4‐PBA upregulates the expression of PPARα and directly binds to PPARα, enhancing its stability 36 . MiR‐483‐5p can suppress the proliferation of HCC via targeting TIMP2 and PPARα, and downregulation of miR‐483‐5p is observed in human HCC tissues 37 . MYC can enhance PPARα target gene Krt23 to promote the proliferation of hepatic cells and the occurrence of HCC 38 .…”

“… 36 MiR‐483‐5p can suppress the proliferation of HCC via targeting TIMP2 and PPARα, and downregulation of miR‐483‐5p is observed in human HCC tissues. 37 MYC can enhance PPARα target gene Krt23 to promote the proliferation of hepatic cells and the occurrence of HCC. 38 As a protein phosphatase, fructose‐1,6‐bisphosphatase 1 has the function of dephosphorylating histone H3T11, inhibiting the expression of PPARα‐mediated β‐oxidation gene and promoting the apoptosis induced by energy stress.…”