Anticancer function of microRNA‐30e is mediated by negative regulation of HELLPAR, a noncoding macroRNA, and genes involved in ubiquitination and cell cycle progression in prostate cancer

Abstract

Prostate cancer (PCa) progression relies on androgen receptor (AR) function, making AR a top candidate for PCa therapy. However, development of drug resistance is common, which eventually leads to development of castration‐resistant PCa. This warrants a better understanding of the pathophysiology of PCa that facilitates the aberrant activation of key signaling pathways including AR. MicroRNAs (miRNAs) function as regulators of cancer progression as they modulate various cellular processes. Here, we demonstrate a multidimensional function of miR‐30e through the regulation of genes involved in various signaling pathways. We noted loss of miR‐30e expression in prostate tumors, which, when restored, led to cell cycle arrest, induction of apoptosis, improved drug sensitivity of PCa cells and reduced tumor progression in xenograft models. We show that experimental upregulation of miR‐30e reduces expression of mRNAs including AR, FBXO45, SRSF7 and MYBL2 and a novel long noncoding RNA (lncRNA) HELLPAR, which are involved in cell cycle, apoptosis and ubiquitination, and the effects could be rescued by inhibition of miR‐30e expression. RNA immunoprecipitation analysis confirmed direct interactions between miR‐30e and its RNA targets. We noted a newly identified reciprocal relationship between miR‐30e and HELLPAR, as inhibition of HELLPAR improved stabilization of miR‐30e. Transcriptome profiling and quantitative real‐time PCR (qRT‐PCR) validation of miR‐30e‐expressing PCa cells showed differential expression of genes involved in cell cycle progression, apoptosis and ubiquitination, which supports our in vitro study. This study demonstrates an integrated function of miR‐30e on dysregulation of miRNA/lncRNA/mRNA axes that may have diagnostic and therapeutic significance in aggressive PCa.

Differential Expression of miRNAs Contributes to Tumor Aggressiveness and Racial Disparity in African American Men with Prostate Cancer

“…Previous studies have shown the tumor suppressor role of miR-30 in various cancers, with this miR-30e being extensively studied and well-characterized [ 17 ]. The relative expression of miR-30e was significantly lower in the tumor tissues compared to the normal tissues [ 23 , 33 ].…”

“…Recently, a multidimensional function of miR-30e through the regulation of genes involved in various signaling pathways was reported. Ganapathy et al observed low expression miR-30e in prostate tumors and experimental upregulation led to cell cycle arrest, apoptosis, drug sensitivity of PCa cells, and reduced tumor progression [ 17 ].…”

“…Prostate tissues obtained by radical prostatectomies were procured in the Cooperative Human Tissue Network (Southern division) at the University of Alabama at Birmingham (UAB) in accordance with an approved IRB protocol. Formalin-fixed and paraffin-embedded (FFPE) tissues from 25 PCa patients, including 10 AA patients, were evaluated by a pathologist, and tumor and adjacent non-involved areas were macro-dissected for RNA extraction followed by qRT-PCR for the expression of candidate miRNAs in patient tissues, as described previously [ 17 , 18 ]. Cases were selected based on the Cancer of the Prostate Risk Assessment (CAPRA)-S score, a prognostic tool for predicting a patient’s risk for biochemical failure following radical prostatectomy [ 19 ].…”

Revealing metastatic castration‐resistant prostate cancer master regulator through lncRNAs‐centered regulatory network

“…Previous research has documented the high expression of this lncRNA in PCa and its role as a ceRNA (competing endogenous RNA) of miR‐30e in PCa cells. MiR‐30e targets several mRNAs, including the AR gene 66 . Moreover, HELLPAR can interact with proteins involved in RNA splicing and ribosome roles, which are essential processes that drive cellular proliferation and tumorigenesis 67 .…”

Identification of F-Box/SPRY Domain-Containing Protein 1 (FBXO45) as a Prognostic Biomarker for TMPRSS2–ERG-Positive Primary Prostate Cancers

“…FBX045 might also play a role in this context. A recent study showed that FBXO45 is downregulated by the tumour-suppressive microRNA-30e [ 38 ]. Overexpression of FBX045 might be driven by the downregulation of microRNA-30e in PCA.…”