Expression of lncRNA MIR222HG co-transcribed from the miR-221/222 gene promoter facilitates the development of castration-resistant prostate cancer

Abstract

Mechanisms by which non-coding RNAs contribute to the progression of hormone-sensitive prostate cancer (PCa) (HSPC) to castration-resistant PCa (CRPC) remain largely unknown. We previously showed that microRNA-221/222 is up-regulated in CRPC and plays a critical role in modulating androgen receptor function during CRPC development. With further investigation, we characterized a putative promoter region located 23.3 kb upstream of the miR-221/222 gene, and this promoter is differentially activated in CRPC LNCaP-Abl cells, leading to the up-regulation of miR-221/222. Upon promoter activation, a set of polyadenylated long non-coding RNA (lncRNA) MIR222HGs was transcribed from this promoter region. Over-expression of these MIR222HGs increased androgen-independent cell growth and repressed the expression of androgen receptor-regulated dihydrotestosterone (DHT)-induced KLK3, TMPRSS2, and FKBP5 in HSPC LNCaP cells, hallmarks of the CRPC phenotype. Clinically, increased expression of MIR222HG is associated with PCa progression to CRPC. In primary tumors, expression levels of MIR222HG and miR-221/222 inversely correlate with Gleason score and androgen receptor (AR) pathway activity. Interestingly, MIR222HG is Argonaute 2-bound and its expression is Dicer 1-dependent, suggesting its functional association with the RNA-induced silencing complex. Further studies led to the hypothesis that MIR222HG may potentially affect miR-mediated expression silencing, subsequently leading to AR reprogramming. Our study highlights an essential role of a non-coding RNA in CRPC development and that differential activation of a single promoter can up-regulate two different types of non-coding RNAs, miR-221/222 and lncRNA MIR222HG, in CRPC. Additionally, this study reveals a novel function of lncRNAs as a modulator of Argonaute-mediated RNA-induced silencing complex.

miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro

“…Functionally, miR-221 targeted HECTD2 and RAB1A in castration-resistant LNCaP subclones, which modulates androgen receptor-mediated signaling and favors the progression to a castration-resistant state [14]. With this in view, miR-221/miR-222 overexpression as part of an escape from VEGFR2 inhibition could be well in line with publications demonstrating oncogenic roles of miR-221 and miR-222 in PCa cells [13][14][15][16].…”

“…On a molecular basis, there are conflicting data regarding miR-221-3p function in PCa cells. While our group could show that restoration of miR-221-3p expression had a tumour suppressive role in castration-resistant DU145 and PC3 cells [12], other researchers demonstrated that miR-221-3p also acted as an oncogene in LNCaP and PC3 cells by supporting progress to a castration-resistant state [13][14][15][16].…”

Long noncoding RNA SNHG20 promotes prostate cancer progression via upregulating DDX17

“…As a class of novel regulatory RNAs, lncRNAs are revealed to have various roles in PCa [50][51][52][53][54]. LncRNA TMPO-AS1 is reported to promote PCa cell proliferation and migration [50].…”

“…LncRNA LINC00844 prevents PCa cell migration 10 Arch Med Sci and invasion via facilitating androgen receptor binding to the chromatin [52]. LncRNA MIR222HG facilitates PCa development via affecting miR-NAs-mediated expression silencing [53]. LncRNA SChLAP1 promotes aggressive PCa via antagonizing the SWI/SNF complex [54].…”

Long non‐coding RNA CCAT1/miR‐148a/PKCζ prevents cell migration of prostate cancer by altering macrophage polarization

“…So far, various lncRNA has been reported to involved in the pathogenesis of PCa, such as SNHG7, MIR222HG, PVT1, and HOTAIR . The dysregulated lncRNAs allows us to identify the mechanism clearly, and also provide help for the further PCa therapy.…”