<p>miR-135b-5p Suppresses Androgen Receptor-Enhanced Hepatocellular Carcinoma Cell Proliferation via Regulating the HIF-2α/c-Myc/P27 Signals in vitro</p>

Abstract

Introduction: Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancers and is ranked as the fifth most common malignancy. Androgen receptor (AR) may promote the progression of HCC at an early stage of the disease. However, this study identified miR-135b-5p as an AR upstream regulator can suppress AR protein expression and inhibit HCC proliferation, consistent with the idea that AR expression is negatively correlated with HCC progression. Methods: The target microRNAs were predicted using online databases (TargetScan, miRDB, and MicroCosm Targets). Cell proliferation ability was measured by MTT and colony formation assay. Western blot was performed to analyze the expression levels of AR, HIF-2α, c-Myc, and p27, which are related to HCC proliferation. Chromatin immunoprecipitation (ChIP) assay and luciferase reporter assay were carried out to investigate the mechanism by which miR-135b-5p decreases AR expression. Results: miR-135b-5p suppresses HCC cell proliferation and AR expression. Downregulation of AR expression by miR-135b-5p may in turn transcriptionally modulate HIF-2α expression via direct binding of AR to the androgen response element (ARE) in the HIF-2α promoter. Further dissection of the mechanism revealed that AR-modulated HIF-2α could suppress c-Myc expression resulting in increased p27 expression that likely contributes to the suppression of proliferation in HCC cells. Conclusion: miR-135b-5p suppresses HCC cell proliferation via targeting AR-modulated HIF-2α/c-Myc/p27 signals, which may help to develop more effective therapies to prevent HCC progression.

Whole‐Transcriptome Sequencing Combined with High‐Dimensional Proteomic Technologies Reveals the Potential Value of miR‐135b‐5p as a Biomarker for Hepatocellular Carcinoma

“…miR-135b-5p was reported to promote tumor progression in colorectal, gastric, and pancreatic cancers [ 50 – 52 ]. However, another study demonstrated that miR-135b-5p acts as a suppressor in HCC by inhibiting androgen receptor expression [ 53 ]. Androgen receptors appear to be differentially expressed in HCC [ 54 ].…”

EGR1 promoted anticancer effects of Scutellarin via regulating LINC00857/miR‐150‐5p/c‐Myc in osteosarcoma

“…Accumulating studies have revealed that c‐Myc has been characterized as a vital oncogene, which is correlated with cell proliferation, apoptosis and metastasis in various human cancers. In human hepatocellular carcinoma, the downregulation of c‐Myc inhibited tumour proliferation 33 . In osteosarcoma, c‐Myc has been shown to promote the growth of tumour cellsss 34 .…”

The role of sex hormones and receptors in HBV infection and development of HBV‐related HCC

“…For example, miR-135b-5p is an upstream regulator of AR, which can suppress HCC cell proliferation by downregulating the AR-mediated HIF-2α/c-Myc/p27 signaling pathway. 79 Additionally, miR-92a-2-5p can suppress AR expression and activate the PHLPP/p-AKT/β-catenin signaling pathway to promote HCC cell invasion. 80 The expression of the long-intergenic-noncoding RNA776 (LINC00667) is upregulated in HCC tissues and cell lines.…”

“…Some microRNAs have been reported to be involved in the regulation of AR. For example, miR‐135b‐5p is an upstream regulator of AR, which can suppress HCC cell proliferation by downregulating the AR‐mediated HIF‐2α/c‐Myc/p27 signaling pathway 79 . Additionally, miR‐92a‐2‐5p can suppress AR expression and activate the PHLPP/p‐AKT/β‐catenin signaling pathway to promote HCC cell invasion 80 .…”