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.
Highlights
For over half a century, androgen deprivation has been the standard therapy for advanced and metastatic prostate cancer, as tumors are initially dependent on androgens for survival and growth
The miR-23b/-27b cluster was ectopically expressed using a lentiviral vector in two independent highly aggressive castration-resistant prostate cancer cell lines, ALVA31 and PC3-ML. 72 hours following transduction, cells were analyzed for GFP expression using flow cytometry in order to determine transduction efficiency for each experiment (S1)
E-cadherin Protein Levels and Reduces Rac1 Activity To understand the molecular mechanisms of miR-23b/-27b mediated inhibition of metastatic phenotypes, we examined the expression of key factors in cancer cell migration and invasion
Summary
For over half a century, androgen deprivation has been the standard therapy for advanced and metastatic prostate cancer, as tumors are initially dependent on androgens for survival and growth. Metastasis, a hallmark of malignancy, is the migration of tumor cells via the bloodstream or lymph system from the original tumor site to distant organs. Metastatic development proceeds through a multistep process that includes local invasion, movement into the bloodstream (intravasation), survival in the circulation, exit from blood vessels (extravasation), initiation and maintenance of micrometastases at distant sites and vascularization of the new tumors [1]. The median survival for patients with localized prostate cancer is greater than 5 years, whereas men with metastatic disease have substantially diminished survival rates [1]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
