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

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 beta (ER beta) 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 ER beta expression. In this study, we further demonstrated that treatment with sunitinib, as well as axitinib, another TKI, could induce ER beta expression in RCC cell lines. Clinical clear cell RCC (ccRCC) patients with higher ER beta expression are more likely to be found VE-cadherin positive and VM positive. Mechanism dissection showed that TKI- induced ER beta 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-pretreatmentinduced RCC VM formation, reduces metastases and improves survival in an experimental orthotopic animal model. Targeting ER beta/circDGKD signals may improve the TKI efficacy and provide novel combination therapies for metastatic RCC.

Automated summary

Vasculogenic mimicry (VM), an alternative channel for tumor nutrient supply, is associated with poor prognosis in renal cell carcinoma (RCC). Sunitinib, a tyrosine kinase inhibitor (TKI), has been reported to induce VM formation by up-regulating estrogen receptor beta (ERβ) expression. This study showed that treatment with sunitinib and another TKI, axitinib, also induced ERβ expression in RCC cell lines. Clinical RCC patients with higher ERβ expression were more likely to have VM. Mechanistically, TKI-induced ERβ up-regulated the circular RNA DGKD, which enhanced VM formation by increasing VE-cadherin expression. Targeting circDGKD intercepted sunitinib-induced RCC VM formation and improved survival in an animal model.