Regulatory Role of mir-203 in Prostate Cancer Progression and Metastasis.

Advanced metastatic prostate cancer (PCa) is a fatal disease, with only palliative therapeutic options. Though almost 80% of cases of metastatic PCa present bone metastasis, our current understanding of the molecular mechanisms that govern this metastatic dissemination remains fragmentary. The main objective of the present study was to identify microRNA (miRNA) genes that regulate metastatic PCa. miRNA expression profiling was done in human prostate cell lines to identify dysregulated miRNA components of advanced PCa. miR-203 expression was assessed in prostate carcinoma cell lines and clinical specimens by real-time PCR and in situ hybridization. To assess the biological significance of miR-203, miR-203 was reexpressed in bone metastatic PCa cell lines followed by in vitro and in vivo functional assays. miR-203 expression is specifically attenuated in bone metastatic PCa suggesting a fundamental antimetastatic role for this miRNA. Reintroduction of miR-203 in bone metastatic PCa cell lines suppresses metastasis via inhibition of several critical steps of the metastatic cascade including epithelial-mesenchymal transition, invasion, and motility. Ectopic miR-203 significantly attenuated the development of metastasis in a bone metastatic model of PCa. Importantly, miR-203 regulates a cohort of pro-metastatic genes including ZEB2, Bmi, survivin, and bone-specific effectors including Runx2, a master regulator of bone metastasis. miR-203 is an "antimetastatic" miRNA in PCa that acts at multiple steps of the PCa metastatic cascade via repression of a cohort of prometastatic targets. miR-203 may be an attractive target for therapeutic intervention in advanced PCa.

Saini S ，Majid S ，Yamamura S ，Tabatabai L ，Suh SO ，Shahryari V ，Chen Y ，Deng G ，Tanaka Y ，Dahiya R ... -  《-》

MicroRNA-466 inhibits tumor growth and bone metastasis in prostate cancer by direct regulation of osteogenic transcription factor RUNX2.

Colden M ，Dar AA ，Saini S ，Dahiya PV ，Shahryari V ，Yamamura S ，Tanaka Y ，Stein G ，Dahiya R ，Majid S ... -  《Cell Death & Disease》

HEF1 promotes epithelial mesenchymal transition and bone invasion in prostate cancer under the regulation of microRNA-145.

The principal problem arising from prostate cancer (PCa) is its propensity to metastasize to bones, and it's crucial to understand the mechanism of tumor progression to metastasis in order to develop therapies that may reduce the morbidity and mortality of PCa patients. Although we had identified that microRNA(miR)-145 could repress bone metastasis of PCa via regulating epithelial-mesenchymal transition (EMT) in previous study, it is still unknown how miR-145 regulated EMT. In the present study, we constructed a luciferase reporter system and identified HEF1 as a direct target of miR-145. More importantly, HEF1 was shown to promote migration, invasion and EMT of PC-3 cells, a human PCa cell line originated from a bone metastatic PCa specimen. And HEF1 was also shown to partially mediate miR-145 suppression of EMT and invasion. Furthermore, inhibition of HEF1 repressed bone invasion of PC-3 cells in vivo. Expression of HEF1 was negatively correlated with miR-145 in primary PCa and bone metastatic specimens, but HEF1 was higher in samples which were more likely to commit to bone metastasis or those with higher free prostate-specific antigen (fPSA) levels and Gleason scores. Taken together, these findings indicate that HEF1 promotes EMT and bone invasion in prostate cancer by directly targeted by miR-145, and miR-145 suppresses EMT and invasion, at least in part, through repressing HEF1.

Guo W ，Ren D ，Chen X ，Tu X ，Huang S ，Wang M ，Song L ，Zou X ，Peng X ... -  《-》

Double-negative feedback loop between ZEB2 and miR-145 regulates epithelial-mesenchymal transition and stem cell properties in prostate cancer cells.

Ren D ，Wang M ，Guo W ，Huang S ，Wang Z ，Zhao X ，Du H ，Song L ，Peng X ... -  《-》

Influence of BMPs on the formation of osteoblastic lesions in metastatic prostate cancer.

Feeley BT ，Gamradt SC ，Hsu WK ，Liu N ，Krenek L ，Robbins P ，Huard J ，Lieberman JR ... -  《JOURNAL OF BONE AND MINERAL RESEARCH》