The microRNA -23b/-27b Cluster Suppresses the Metastatic Phenotype of Castration-Resistant Prostate Cancer Cells

Abstract

MicroRNAs (miRs) are small, endogenous, non-coding RNAs that regulate the stability and/or translation of complementary mRNA targets. MiRs have emerged not only as critical modulators of normal physiologic processes, but their deregulation may significantly impact prostate and other cancers. The expression of miR-23b and miR-27b, which are encoded by the same miR cluster (miR-23b/-27b), are downregulated in metastatic, castration-resistant tumors compared to primary prostate cancer and benign tissue; however, their possible role in prostate cancer progression is unknown. We found that ectopic expression of miR-23b/-27b in two independent castration-resistant prostate cancer cell lines resulted in suppression of invasion and migration, as well as reduced survival in soft agar (a measure of anoikis). However, there was no effect of miR-23b/-27b on cell proliferation suggesting that these miRs function as metastasis (but not growth) suppressors in prostate cancer. Conversely, inhibition of miR-23b/-27b in the less aggressive androgen-dependent LNCaP prostate cancer cell line resulted in enhanced invasion and migration also without affecting proliferation. Mechanistically, we found that introduction of miR-23b/-27b in metastatic, castration-resistant prostate cancer cell lines resulted in a significant attenuation of Rac1 activity without affecting total Rac1 levels and caused increased levels of the tumor suppressor E-cadherin. Inhibition of these miRs had the opposite effect in androgen-dependent LNCaP cells. These results suggest that miR-23b/-27b are metastasis suppressors that might serve as novel biomarkers and therapeutic agents for castration-resistant disease.

The MicroRNA-23b/27b/24 Cluster Promotes Breast Cancer Lung Metastasis by Targeting Metastasis-suppressive Gene Prosaposin

“…Interestingly, miRNA overexpressing cells reduced transwell migration and decreased Matrigel invasion (Fig. 2D), consistent with previous reports of decreased migration upon ectopic expression of miR-23b in prostate cancer cell lines (19).…”

“…In addition, there are conflicting reports regarding the functional role of the miR-23/27/24 clusters during tumor development and metastatic progression. miR-23b has been shown to decrease migration and invasion in vitro (19) and to decrease colon cancer lung metastasis (20) and breast cancer lymph node metastasis in vivo (21). Conversely, ectopic expression of the entire miR-23a/27a/24 cluster increased migration and invasion in breast cancer cells and promoted hepatic metastasis (22).…”

Downregulation of mir-23b in plasma is associated with poor prognosis in patients with colorectal cancer

“…For example, overexpression of miR-23b has been shown to inhibit migration in prostate cancer cells (16,33), and hepatocellular carcinoma cells (17). In glioma, overexpression of miR-23b significantly inhibited cell migration and invasion while inhibition of miR-23b expression significantly increased migration (18).…”

MicroRNA-27b reverses docetaxel resistance of non-small cell lung carcinoma cells via targeting epithelial growth factor receptor

“…Thereby, suggesting that miR-27b may act as a tumor inhibitor in NSCLC. Previous studies have revealed that miR-27b acts as a tumor suppressor in the development of various malignancies, including prostate cancer, colon cancer and neuroblastoma (24)(25)(26). However, other studies have also indicated that miR-27b may promote tumorigenesis in various cancer types.…”