Androgen receptor promotes renal cell carcinoma (RCC) vasculogenic mimicry (VM) via altering TWIST1 nonsense-mediated decay through lncRNA-TANAR
Bosen You, Yin Sun, Jie Luo, Keliang Wang, Qing Liu, Ruizhe Fang, Bingmei Liu, Fu-Ju Chou, Ronghao Wang, Jialin Meng, Chi‐Ping Huang, Shuyuan Yeh, Chawnshang Chang, Wanhai Xu
Abstract
While the androgen receptor (AR) may influence the progression of clear cell renal cell carcinoma (ccRCC), its role to impact vasculogenic mimicry (VM) to alter the ccRCC progression and metastasis remains obscure. Here, we demonstrated that elevated AR expression was positively correlated with tumor-originated vasculogenesis in ccRCC patients. Consistently, in vitro research revealed AR promoted VM formation in ccRCC cell lines via modulating lncRNA-TANAR/TWIST1 signals. Mechanism dissection showed that AR could increase lncRNA-TANAR (TANAR) expression through binding to the androgen response elements (AREs) located in its promoter region. Moreover, we found that TANAR could impede nonsense-mediated mRNA decay (NMD) of TWIST1 mRNA by direct interaction with TWIST1 5'UTR. A preclinical study using in vivo mouse model with orthotopic xenografts of ccRCC cells further confirmed the in vitro data. Together, these results illustrated that AR-mediated TANAR signals might play a crucial role in ccRCC VM formation and metastasis, and targeting this newly identified AR/TANAR/TWIST1 signaling may help in the development of a novel anti-angiogenesis therapy to better suppress the ccRCC progression.