miRNA-382-5p Suppresses the Expression of Farnesoid X Receptor to Promote Progression of Liver Cancer

Xiaobo Nie; Huiyang Liu; Xiaoyun Wei; Lanqing Li; Linhua Lan; Lili Fan; Han Ma; Lei Liu; Yun Zhou; Ruifang Hou; Wei-Dong Chen

doi:10.2147/CMAR.S324072

miRNA-382-5p Suppresses the Expression of Farnesoid X Receptor to Promote Progression of Liver Cancer

Cancer Manag Res. 2021 Oct 22:13:8025-8035. doi: 10.2147/CMAR.S324072. eCollection 2021.

Authors

Xiaobo Nie¹, Huiyang Liu¹, Xiaoyun Wei¹, Lanqing Li¹, Linhua Lan², Lili Fan¹, Han Ma¹, Lei Liu¹, Yun Zhou¹, Ruifang Hou¹, Wei-Dong Chen^{1

3}

Affiliations

¹ Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, People's Republic of China.
² Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
³ Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, People's Republic of China.

Abstract

Background: The dysregulation of microRNAs (miRNAs) and hepatotoxicity due to the aberrant accumulation of bile acids (BAs) are notorious causes that predispose an individual to the development of hepatocellular carcinoma (HCC). Farnesoid X receptor (FXR), encoded by NR1H4 gene, has been identified as a crucial BA receptor to maintain the homeostasis of BA pool and its expression is decreased in HCC. miR-382-5p plays an important role in the pathogenesis of many human malignancies and was reported to promote the proliferation and differentiation of normal liver cells and liver regeneration. However, there is still some controversy about its role in HCC microenvironment. This study aims to explore the expression pattern of miR-382-5p in HCC and its role in regulating FXR during the development of HCC.

Methods: Tissues collected from 30 HCC patients were subjected to extraction of total RNA and quantitative real-time PCR (qRT-PCR) for the analyses of miR-382-5p expression and NR1H4 mRNA levels, and their expressions were verified by analyzing the online HCC-related GSE datasets. The role of miR-382-5p in regulating cellular proliferation and expression of FXR in different HCC cell lines was analyzed by qRT-PCR, Western Blot, real-time cellular analysis (RTCA) and luciferase reporter assays. The role of miR-382-5p in regulating downstream genes of FXR in HCC cells was also analyzed.

Results: miR-382-5p was upregulated in HCC tissues and inversely associated with the downregulation of NR1H4 mRNA levels. The luciferase reporter assay proved that miR-382-5p directly targeted the 3'-untranslated region (3'-UTR) of human NR1H4 mRNA. Overexpression of miR-382-5p led to a malignant proliferation of HCC cells by suppressing the expression of FXR. In contrast, blocking the endogenous miR-382-5p was sufficient to suppress the cellular proliferation rate of HCC through increasing FXR expression. Additionally, miR-382-5p inhibited the expression of some target genes of FXR, including SHP, FGF19 and SLC51A, and this inhibitory effect was FXR-dependent.

Conclusion: Therefore, miR-382-5p promotes the progression of HCC in vitro by suppressing FXR and could serve as a valuable therapeutic target for HCC treatment.

Keywords: FXR; hepatocellular carcinoma; miRNA-382-5p; proliferation.

Grants and funding

There is no funding to report.