MicroRNA-320 suppresses the stem cell-like characteristics of prostate cancer cells by downregulating the Wnt/beta-catenin signaling pathway

Abstract

Prostate cancer (PCa) is a leading cause of mortality and morbidity in men worldwide, and emerging evidence suggests that the CD44(high) prostate tumor-initiating cells (TICs) are associated with its poor prognosis. Although microRNAs are frequently dysregulated in human cancers, the influence of microRNAs on PCa malignancy and whether targeting TIC-associated microRNAs inhibit PCa progression remain unclear. In this study, we found that miR-320 is significantly downregulated in PCa. Overexpression of miR-320 in PCa cells decreases PCa tumorigenesis in vitro and in vivo. Global gene expression profiling of miR-320-overexpressing PCa cells reveals that downstream target genes of Wnt/β-catenin pathway and cancer stem cell markers are significantly decreased. MicroRNA-320 inhibits β-catenin expression by targeting the 3'-untranslated region of β-catenin mRNA. The reduction of miR-320 associated with increased β-catenin was also found in CD44(high) subpopulation of prostate cancer cells and clinical PCa specimens. Interestingly, knockdown of miR-320 significantly increases the cancer stem-like properties, such as tumorsphere formation, chemoresistance and tumorigenic abilities, although enriching the population of stem-like TICs among PCa cells. Furthermore, increased miR-320 expression in prostate stem-like TICs significantly suppresses stem cell-like properties of PCa cells. These results support that miR-320 is a key negative regulator in prostate TICs, and suggest developing miR-320 as a novel therapeutic agent may offer benefits for PCa treatment.

Histone Deacetylase Inhibition in Prostate Cancer Triggers miR-320–Mediated Suppression of the Androgen Receptor

“…OBP-801 is a cyclic peptide-based HDAC inhibitor derived from a natural product containing a disulfide bond. The IC 50 for the HDAC inhibitory activity of OBP-801, TSA, SAHA, and MS-275 were under or around 1 mmol/L in our study ( Supplementary Fig. S1D).…”

Prostate cancer cell proliferation is suppressed by microRNA‑3160‑5p via targeting of F‑box and WD repeat domain containing 8

“…They participate in numerous cellular processes, including proliferation, differentiation, apoptosis, metastasis, stem cell maintenance and metabolism (13,(23)(24)(25)(26)(27). miRNAs are involved in PCa pathogenesis via the regulation of oncogene upregulation or tumor suppressor downregulation in PCa (13).…”

Pan-cancer methylation and expression profiling of adenocarcinomas revealed epigenetic silencing in the WNT signaling pathway

“…Cancer stem cells (CSC) are thought to drive tumorigenesis and progression. They have the ability to cell-renew and give rise to malignant tumor cells [16] CSCs may require an intricate balance in the WNT pathway activity: on the one hand, they may require WNT activation to trigger self-renewal [17]; on the other hand, they may need to inhibit WNT pathway to suppress developmental processes to retain their stem-cell state [18]. This could potentially explain why we observed methylation and epigenetic silencing in known WNT inhibitors, such as SFRP1, WIF1, and DKK1, as well as WNT activating components, such as WNT3A, FZD10, and PRKCB, in adenocarcinomas.…”