Abstract
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.
Highlights
Prostate cancer (PCa) is the most common male malignancy and the second leading cause of cancer death among men in the United States
Conclusions: 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
We have shown that miR-203 suppresses prostate cancer progression and metastasis via repression of a cohort of prometastatic targets. miR-203 expression is attenuated in bone metastatic cell lines and clinical specimens supporting a fundamental "antimetastatic" role of this miRNA
Summary
Prostate cancer (PCa) is the most common male malignancy and the second leading cause of cancer death among men in the United States. Significant gains have been made in the management of the early phases of PCa, the evolution of PCa to a hormone-independent stage invariably signals advanced metastatic disease, with limited therapeutic options and poor prognosis [1]. Metastasis involves multiple sequential steps including the escape of neoplastic cells from a primary tumor (local invasion), intravasation into the systemic circulation, survival during transit through the vasculature, extravasation into distant tissues, and proliferation at a new site [2]. Advanced PCa is mostly associated with metastatic dissemination, typically to the bones [4], causing both osteoblastic and osteolytic lesions [5]. The mechanisms by which PCa cells selectively metastasize to the bone remain largely unknown. Understanding molecular controls that signal PCa progression and metastasis is a key to develop better therapeutic and diagnostic interventions for the disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
