Targeting circDGKD Intercepts TKI’s Effects on Up-Regulation of Estrogen Receptor β and Vasculogenic Mimicry in Renal Cell Carcinoma

Cancers

Guang-Qian Xiao¹  Chawnshang Chang²  Jie Luo²  Shuyuan Yeh²  Yin Sun²  Wei-Wei Yu²  Hao-Jie Chen³  Jie Ding³  Xin-Gang Cui³  Jun Qi³ 

[1] Department of Pathology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA;George H. Whipple Lab for Cancer Research, Departments of Urology, Pathology and the Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA;Urology Department, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China;

关键词: estrogen receptor β;    vasculogenic mimicry;    renal cell carcinoma;    circular RNA;    VE-cadherin;   

DOI  :  10.3390/cancers14071639

来源: DOAJ

【 摘 要 】

Vasculogenic mimicry (VM) has been reported as an alternative channel to increase tumor nutrient supplies and accelerate tumor progression, and is associated with poor survival prognosis in multiple cancers, including renal cell carcinoma (RCC). The currently used anti-angiogenic treatment for metastatic RCC, sunitinib, a tyrosine kinase inhibitor (TKI), has been reported to induce VM formation. Previously we identified that the estrogen receptor β (ERβ) functions as an oncogenic factor to promote RCC progression, supported by the analytic results from The Cancer Genome Atlas (TCGA) database. We have also found evidence that sunitinib induces RCC VM formation by up-regulating ERβ expression. In this study, we further demonstrated that treatment with sunitinib, as well as axitinib, another TKI, could induce ERβ expression in RCC cell lines. Clinical clear cell RCC (ccRCC) patients with higher ERβ expression are more likely to be found VE-cadherin positive and VM positive. Mechanism dissection showed that TKI- induced ERβ transcriptionally up-regulates the circular RNA of DGKD (circDGKD, hsa_circ_0058763), which enhances VE-cadherin expression by sponging the microRNA miR-125-5p family. Targeting circDGKD intercepts sunitinib-pretreatment-induced RCC VM formation, reduces metastases and improves survival in an experimental orthotopic animal model. Targeting ERβ/circDGKD signals may improve the TKI efficacy and provide novel combination therapies for metastatic RCC.

【 授权许可】

Unknown