MicroRNA-383 located in frequently deleted chromosomal locus 8p22 regulates CD44 in prostate cancer

Abstract

A major genomic alteration in prostate cancer (PCa) is frequent loss of chromosome (chr) 8p with a common region of loss of heterozygosity (LOH) at chr8p22 locus. Genomic studies implicate this locus in the initiation of clinically significant PCa and with progression to metastatic disease. However, the genes within this region have not been fully characterized to date. Here we demonstrate for the first time that a microRNA component of this region –miR-383- is frequently downregulated in prostate cancer, plays a critical role in determining tumor initiating potential and is involved in prostate cancer metastasis via direct regulation of CD44, a ubiquitous marker of PCa tumor initiating cells (TICs)/ stem cells. Expression analyses of miR-383 in PCa clinical tissues established that low miR-383 expression is associated with poor prognosis. Functional data suggests that miR-383 regulates PCa tumor initiating/ stem-like cells via CD44 regulation. Ectopic expression of miR-383 inhibited tumor initiating capacity of CD44+ PCa cells. Also, ‘anti-metastatic’ effects of ectopic miR-383 expression were observed in a PCa experimental metastasis model. In view of our results, we propose that frequent loss of miR-383 at chr8p22 region leads to tumor initiation and prostate cancer metastasis. Thus, we have identified a novel finding that associates a long observed genomic alteration to PCa stemness and metastasis. Our data suggests that restoration of miR-383 expression may be an effective therapeutic modality against PCa. Importantly, we identified miR-383 as a novel PCa tissue diagnostic biomarker with a potential that outperforms that of serum PSA.

Circulating microRNAs as potential diagnostic biomarkers and therapeutic targets in prostate cancer: Current status and future perspectives

“…Experimental data recommended that this miRNA contributed with PCa metastasis through direct regulation of CD44, a marker of PCa tumorinitiating cells/stem cells. 91 Mishra et al 92 demonstrated a miR-21 association with androgen receptor (AR) signaling pathway. AR crossestalk with TGFβ signaling pathway has a critical role in cell survival and proliferation roles in PCa.…”

miR‐383 promotes cholangiocarcinoma cell proliferation, migration, and invasion through targeting IRF1

“…Similarly, Zhao et al 18,19 found that patients with lung cancer with low expression of miR-383-5p had a markedly reduced overall survival and disease-free survival rate compared with those with high expression of miR-383-5p. Besides, the poor prognostic value of miR-383 was also observed in patients with prostate cancer 21 and patients with ependymoma. Besides, the poor prognostic value of miR-383 was also observed in patients with prostate cancer 21 and patients with ependymoma.…”

“…13 Therefore, we assumed that IRF1 is a target of miR-383. 18,19 The antitumor effect of miR-383 was also found in colon cancer, 20 prostate cancer, 21 and esophageal cancer. We found that miR-383 expression was negatively related to IRF1 mRNA and protein expression in cholangiocarcinoma tissue samples, and miR-383 negatively regulated IRF1 mRNA and protein expression in cholangiocarcinoma cells.…”

EGCG inhibits CSC‐like properties through targeting miR‐485/CD44 axis in A549‐cisplatin resistant cells

“…For example, increased expression of CD44 indicates more aggressive behavior in clear cell renal cell carcinoma . In prostate cancer, miR‐383 can regulate tumor‐initiating/stem‐like cells via regulating CD44 . miR‐143 can target CD44 to suppress breast cancer progression and CSC‐like properties .…”