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

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 3ʹ-untranslated region (3ʹ-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.

miR-382-5p promotes cell invasion in hepatocellular carcinoma by targeting PTEN to activate PI3K/Akt signaling pathway

“…The above results suggest that miR-382-5p expression was upregulated in both HCC tissues and cell lines, which are consistent with the miR-382-5p expression in breast cancer [ 11 ] and acute lymphocytic leukemia [ 12 ]. It is consistent with the results reported by Xiaobo NIE [ 22 ] and Juan Du [ 23 ].…”

“…Previous studies have reported the role of miR-382-5p in various tumors. Xiaobo NIE [ 22 ] has reported that miR-382-5p is highly expressed in liver cancer tissues. miR-382-5p promotes the progression of HCC in vitro by suppressing FXR and could serve as a valuable therapeutic target for HCC treatment.…”

miR-382-5p promotes breast cancer invasion via the regulation of PTEN

“…Even though miR-382-5p has been found in a variety of human cancers, its exact role in tumor development is unknown 13,16,33 . It was reported that miR-382-5p promoted breast cancer cell proliferation, migration, and invasion through the RERG/Ras/ERK signaling axis 11 .…”

“…Non-coding RNAs (ncRNAs) account for 98% of the human genome and are classi ed into two types based on size and function: long non-coding RNAs and small non-coding RNAs 5,6 .MicroRNAs (miRNAs) are small non-coding RNA molecules that have 19-24 nucleotides in length and perform various regulatory functions to regulate target gene expression on post-transcriptional levels 7 .Different studies show that miRNAs have an oncogenic or tumor suppressor effect in cancer by modifying biological processes such as cell cycle, cell proliferation, metabolic activity, autophagy, invasion, and cell death 8-10 . Ho, J. Y. et al discovered that miR-382-5p had the highest expression ratio of the screened miRNAs and that miR-382-5p overexpression promoted breast cancer proliferation, migration, invasion, and metastasis 11 .In addition, miR-382-5p up-regulation was previously identi ed to play oncogenic roles by promoting the tumor cells' development in breast cancer 12 .Similarly, the alternation of miR-382-5P has been detected in Osteosarcoma (OS) 13 Hepatocellular carcinoma (HCC) 14,15 , and acute lymphocytic leukemia 16 .…”

Clinical significance and oncogenic function of NR1H4 in clear cell renal cell carcinoma

“…NR1H4 involved in several biological processes, including lipogenesis, gluconeogenesis, ammonia detoxification, glycogen synthesis, bile acid metabolism and inflammation [7,8]. Recently, NR1H4 has been reported in multiple cancers, including colorectal cancer (CRC), hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), breast cancer, cholangiocarcinoma, cervical cancer [9][10][11][12][13][14]. Shan Li.…”