Research Highlights

LuzheSun
Luzhe Sun, Ph.D.

Transforming growth factor (TGFß) has been shown to suppress tumor development in the early stages of tumor progression, but when there is either a loss or reduction of TGFß receptor expression in tumor cells, it creates a growth advantage to early growing tumors. For example, prostate cancer cells frequently escape growth inhibition from TGFß by downregulating TGFß receptor II (TGFBR2). However, the molecular mechanism regulating the loss of TGFBR2 in advanced prostate cancer remains unclear. Through the analysis of published and our own data, we found an inverse correlation between the expression levels of TGFBR2 and androgen receptor (AR), and AR signaling can down-regulate TGFBR2 expression. To investigate how AR signaling may inhibit TGFBR2 expression, we tested the hypothesis that the loss of expression of TGFBR2 might be due to the complementary binding of some microRNAs with specific nucleotide sequences in the untranslated region (UTR) of TGFBR2 mRNA. Interestingly, it has been reported that activated AR directly activates the transcription of microRNA-21 (miR-21). The results of our research showed that miR-21 suppresses TGFBR2 levels by binding to its 3'-UTR and that AR signaling further improves the effect. We observed that AR-positive cancer cell lines expressed relatively higher levels of miR-21 compared to AR-negative cells. We found that miR-21 was able to greatly reduce the responsiveness of prostate cells to TGFß-mediated downstream Smad phosphorylation, cell growth suppression, apoptosis and migration in vitro. An analysis of primary prostate cancers showed that increased miR-21/AR expression correlated with significantly reduced expression of TGFBR2. Manipulating androgen signaling or the expression levels of AR or miR-21 reduced TGFBR2 expression in human prostate epithelial cells, human prostate cancer xenografts, and mouse prostate glands. Furthermore, we found that miR-21 and AR regulated mutual expression resulting in a positive feedback loop. In particular, AR positively regulates miR-21 expression. This miR-21/AR-positive feedback signaling axis can make tumor cells addicted to AR signaling for their malignant growth. Thus targeting miR-21 alone or in combination with AR may constitute a novel therapeutic approach by not only blocking their tumor-promoting effects but also restoring the tumor inhibitory effect of TGFß in prostate cancer.

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