TR4 nuclear receptor promotes clear cell renal cell carcinoma (ccRCC) vasculogenic mimicry (VM) formation and metastasis via altering the miR490-3p/vimentin signals
TR4 nuclear receptor promotes clear cell renal cell carcinoma (ccRCC) vasculogenic mimicry (VM) formation and metastasis via altering the miR490-3p/vimentin signals
复制标题
DOI：
10.1038/s41388-018-0269-1
复制
发表时间：
2018-11-01
期刊：
影响因子：
8
通讯作者：
Chang, Chawnshang
中科院分区：
文献类型：
--
作者：
Bai, Jian;Yeh, Shuyuan;Chang, Chawnshang
虽然TR4核受体在促进前列腺癌进展中起关键作用，但其在透明细胞肾细胞癌（clear cell renal cell carcinoma, ccRCC）进展中的作用尚不清楚。本研究表明，TR4可通过调节miR490-3p/vimentin （VIM）信号，促进ccRCC细胞血管生成模拟（VM）的形成及其相关转移。机制解剖发现，TR4可能通过直接结合miR-490-3p启动子区域的TR4-response-element (TR4REs)，降低miR-490-3p的表达，从而增加致癌基因VIM的表达，进而直接靶向VIM- mrna的3′UTR，增加其蛋白表达。在裸鼠肾亚囊移植RCC Caki-1细胞的体内小鼠模型的临床前研究也发现，TR4可通过调节miR490-3p/VIM信号促进ccRCC VM及其相关转移。基于多种RCC细胞系和体内小鼠模型的临床前研究结果均表明，TR4可能在促进ccRCC VM形成和转移中发挥关键作用，用小分子靶向新发现的TR4/miR-490-3p/VIM信号可能有助于我们开发新的治疗方法，更好地抑制ccRCC转移。
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.