Exosomal lincROR promotes docetaxel resistance in prostate cancer through a β-catenin/HIF-1α positive feedback loop.

Emerging evidence have suggest that patients with metastatic prostate cancer (PCa) will become resistant after receiving docetaxel chemotherapy, but the specific regulatory mechanism is still unclear. LincROR is an important oncogenic lncRNA which plays an important role in regulating tumor carcinogenesis and metastasis; however, the underlying mechanism of lincROR functioning in the docetaxel resistance process of PCa remains largely unknown. In the present study, we found that lincROR is highly expressed in docetaxel-resistant PCa cell lines and was associated with poor docetaxel response in metastatic PCa patients. By using loss- and gain-of-function experiments revealed that lincROR promotes PCa cells growth and docetaxel resistance in vitro and in vivo. Mechanistic studies demonstrated that lincROR specifically interacts with and stabilizes MYH9 protein, which enhances β-catenin/hypoxia-inducible factor 1-alpha (HIF-1α) pathways. Besides, HIF-1α could bind with the promoter region of lincROR to activate its transcription, thus forming the lincROR/MYH9/HIF-1α positive feedback loop. Moreover, lincROR could be packaged into exosomes in an hnRNPA1-dependent manner and then disseminated chemoresistance phenotype to receipt cells. Overall, our study provides evidence supporting exosome-mediated lincROR activates the β-catenin/HIF-1α positive feedback loop by targeting MYH9 protein, which may be exploited for anticancer therapy. Implications: Our findings suggest that targeting hypoxia stress and chemoresistance for therapeutic purposes, and lincROR could promote the improvement of treatment responses in DTX-resistant PCa patients.