Premium
Preclinical studies using miR‐32‐5p to suppress clear cell renal cell carcinoma metastasis via altering the miR‐32‐5p/TR4/HGF/Met signaling
Author(s) -
Wang Mingchao,
Sun Yin,
Xu Junjie,
Lu Jieyang,
Wang Kefeng,
Yang DongRong,
Yang Guosheng,
Li Gonghui,
Chang Chawnshang
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31289
Subject(s) - clear cell renal cell carcinoma , cancer research , metastasis , microrna , mmp2 , small hairpin rna , biology , signal transduction , cell migration , cell culture , medicine , cancer , renal cell carcinoma , microbiology and biotechnology , gene knockdown , biochemistry , genetics , gene
While testicular nuclear receptor 4 (TR4) may promote prostate cancer (PCa) metastasis, its role in the clear cell renal cell carcinoma (ccRCC) remains unclear. Here we found a higher expression of TR4 in ccRCC tumors from patients with distant metastases than those from metastasis‐free patients, suggesting TR4 may play positive roles in the ccRCC metastasis. Results from multiple in vitro ccRCC cell lines also confirmed TR4's positive roles in promoting ccRCC cell invasion/migration via altering the microRNA (miR‐32‐5p)/TR4/HGF/Met/MMP2‐MMP9 signaling. Mechanism dissection revealed that miR‐32‐5p could suppress TR4 protein expression levels via direct binding to the 3′UTR of TR4 mRNA, and TR4 might then alter the HGF/Met signaling at the transcriptional level via direct binding to the TR4‐response‐elements (TR4RE) on the HGF promoter. Then the in vitro data also demonstrated the efficacy of Sunitinib, a currently used drug to treat ccRCC, could be increased after targeting this newly identified miR‐32‐5p/TR4/HGF/Met signaling. The preclinical study using the in vivo mouse model with xenografted ccRCC cells confirmed the in vitro cell lines data. Together, these findings suggest that TR4 is a key player to promote ccRCC metastasis and targeting this miR‐32‐5p/TR4/HGF/Met signaling with small molecules including TR4‐shRNA or miR‐32‐5p may help to develop a new therapy to better suppress the ccRCC metastasis.