Androgen receptor decreases renal cell carcinoma bone metastases via suppressing the osteolytic formation through altering a novel circEXOC7 regulatory axis

Background Clear cell renal cell carcinoma (ccRCC) has gender differences, with the androgen receptor (AR) linked positively with metastasis to the lung. Its linkage to ccRCC bone metastases (RBMs), however, remains unclear. Methods In the current study, five human RCC and five RCC bone metastasis tissues were deeply sequenced using Arraystar human circRNA V2.0 microarray. We conducted gain-of-function screening in vitro and in vivo to elucidate the AR's role in the RBM. Loss/gain-of-function was also implemented to verify the roles of related non-coding RNAs and proteins. Results We uncovered that RBM also has a gender difference showing higher AR expression may be linked to fewer RBMs, which might involve suppressing osteolytic formation. Mechanism dissection indicates that AR can decrease the circular RNA EXOC7 (circEXOC7), expression via enhancing transcription of DHX9, a regulatory protein in circRNA biogenesis. The circEXOC7 can sponge/suppress miR-149-3p resulting in suppressing the CSF1 expression by directly binding to the 3 ' UTR region of CSF1 mRNA. Results from clinical epidemiological surveys also found that AR has a positive correlation with miR-149-3p and a negative correlation with CSF1 in AR-positive ccRCC tissues. Preclinical studies with Balb/c nude mouse model also validated that targeting this newly verified AR/DHX9/circEXOC7/miR-149-3p/CSF1 signaling via altering circEXOC7 or AR could lead to suppressing the RBM progression. Conclusions These data showed that AR/DHX9/circEXOC7/miR-149-3p/CSF1 signaling acts as a valuable feature in the bone metastasis of renal cancer, which may benefit in suppressing the RBM progression.