While TR4 nuclear receptor plays key roles to promote prostate cancer progression, its roles to alter the progression of clear cell renal cell carcinoma (ccRCC), remains unclear. Here, we demonstrate that TR4 can promote the ccRCC cell vasculogenic mimicry (VM) formation and its associated metastasis via modulating the miR490-3p/vimentin (VIM) signals. Mechanism dissection revealed that TR4 might increase the oncogene VIM expression via decreasing the miR-490-3p expression through direct binding to the TR4-response-elements (TR4REs) on the promoter region of miR-490-3p, which might then directly target the 3' UTR of VIM-mRNA to increase its protein expression. Preclinical studies using the in vivo mouse model with xenografted RCC Caki-1 cells into the sub-renal capsule of nude mice also found that TR4 could promote the ccRCC VM and its associated metastasis via modulating the miR490-3p/VIM signals. Together, results from preclinical studies using multiple RCC cell lines and the in vivo mouse model all conclude that TR4 may play a key role to promote ccRCC VM formation and metastasis and targeting the newly identified TR4/miR-490-3p/VIM signals with small molecules may help us to develop a new therapeutic approach to better suppress the ccRCC metastasis.

Background/Aims: Previous results on the association between MTR gene A2756G polymorphism and PCa risk are inconclusive.Methods: We used odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) to evaluate the correlation between MTR A2756G polymorphism and risk of PCa in meta-analysis. Serum expression of MTR was detected by ELISA and in-silico tools were utilized to assess this variant.Results: Our study included 2,921 PCa patients and 3,095 control subjects. The results indicated that the MTR A2756G polymorphism is linked with an increased risk of PCa using three genetic models (G-allele vs. A-allele: OR = 1.16, 95%CI = 1.04 - 1.30; GA vs. AA: OR = 1.17, 95%CI = 1.02 - 1.33; GG+GA vs. AA: OR = 1.18, 95%CI = 1.04 - 1.34). Stratified analysis produced similar results. A significant association was also indicated in advanced PCa from the meta-analysis. Finally, our experiments showed evidence that serum MTR levels in PCa patients with AA genotypes were statistically higher than in those with GG/GA genotypes.Conclusions: Our present study suggests that the MTR A2756G polymorphism may contribute to the risk of developing PCa, particularly in Asian and hospital-based studies. Moreover, serum MTR might be utilized in diagnosis of PCa.

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