Exosomal lincROR Promotes Docetaxel Resistance in Prostate Cancer through a β-catenin/HIF1α Positive Feedback Loop

Abstract Emerging evidence has suggested that patients with metastatic prostate cancer will become resistant after receiving docetaxel (DTX) chemotherapy, but the specific regulatory mechanism is still unclear. lincROR is an important oncogenic long noncoding RNA which plays an important role in regulating tumor carcinogenesis and metastasis; however, the underlying mechanism of lincROR functioning in the DTX resistance process of prostate cancer remains largely unknown. In the current study, we found that lincROR is highly expressed in DTX-resistant prostate cancer cell lines and was associated with poor DTX response in patients with metastatic prostate cancer. By using loss- and gain-of-function experiments revealed that lincROR promotes prostate cancer cells growth and DTX 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 (HIF1α) pathways. Besides, HIF1α could bind with the promoter region of lincROR to activate its transcription, thus forming the lincROR/MYH9/HIF1α positive feedback loop. Moreover, lincROR could be packaged into exosomes in an heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1)-dependent manner and then disseminated chemoresistance phenotype to receipt cells. Overall, our study provides evidence supporting exosome-mediated lincROR activates the β-catenin/HIF1α 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 patients with DTX-resistant prostate cancer.