Androgen receptor promotes renal cell carcinoma (RCC) vasculogenic mimicry (VM) via altering TWIST1 nonsense-mediated decay through lncRNA-TANAR

Bosen You,Qing Liu,Yin Sun,Bingmei Liu,Keliang Wang,Ruizhe Fang,Wanhai Xu,Jialin Meng,Jie Luo,Chawnshang Chang,Chi-Ping Huang,Ronghao Wang,Shuyuan Yeh,Fuju Chou

doi:10.1038/s41388-020-01616-1

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.

Highlights

Clear cell renal cell carcinoma, the major subtype of aggressive human malignancies, accounted for approximately 1,000,000 cases and 175,000 deaths worldwide in 2018 [1]
The vasculogenic mimicry (VM) was significantly higher in Stage II and Stage III compared with Stage I (Fig. 1b)
To examine the role of TWIST1 in Clear cell renal cell carcinoma (ccRCC) clinical samples, we detected its expression by IHC in 23 pairs of samples derived from ccRCC tumors and adjacent normal tissues (Fig. 2j) and the results showed a higher expression of TWIST1 was detected in tumors than in paired adjacent normal tissues (p < 0.001; n = 23) (Fig. 2k), which was consistent with the results extracted from the cancer genome atlas (TCGA) mRNA database (Fig. 2l)

Summary

Introduction

Clear cell renal cell carcinoma (ccRCC), the major subtype of aggressive human malignancies, accounted for approximately 1,000,000 cases and 175,000 deaths worldwide in 2018 [1]. For most metastatic RCC, anti-angiogenesis therapy, such as treatment with sunitinib and pazopanib, as well as with vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI), has proved its efficacy. The androgen receptor (AR) can promote progression and hematogenous metastasis in ccRCC through ASS1P3/ miR-34a-5p/ASS1 and miR-185-5p/HIF-2a/VEGF signaling, respectively [5, 6]. This is consistent with the higher incidence and more malignant phenotypes in males according to data from the surveillance epidemiology and Androgen receptor promotes renal cell carcinoma (RCC) vasculogenic mimicry (VM) via altering TWIST1

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Conclusion