Preclinical studies using miR‐32‐5p to suppress clear cell renal cell carcinoma metastasis via altering the miR‐32‐5p/TR4/HGF/Met signaling

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, su...

Full description

Saved in:
Bibliographic Details
Published in:International journal of cancer 2018-07, Vol.143 (1), p.100-112
Main Authors: Wang, Mingchao, Sun, Yin, Xu, Junjie, Lu, Jieyang, Wang, Kefeng, Yang, Dong‐Rong, Yang, Guosheng, Li, Gonghui, Chang, Chawnshang
Format: Article
Language:English
Subjects:
3' Untranslated Regions
Animals
Biotechnology
c-Met protein
Cancer
Carcinoma, Renal Cell - genetics
Carcinoma, Renal Cell - metabolism
Carcinoma, Renal Cell - pathology
Cell Line, Tumor
Cell lines
Cell migration
Cell Movement - drug effects
Cell Survival - drug effects
Clear cell-type renal cell carcinoma
Gelatinase A
Gelatinase B
Gene Expression Regulation, Neoplastic - drug effects
Hepatocyte Growth Factor - genetics
HGF/Met
Humans
Kidney cancer
Kidney Neoplasms - genetics
Kidney Neoplasms - metabolism
Kidney Neoplasms - pathology
Medical research
Metastases
Metastasis
Mice
microRNA
MicroRNAs - genetics
miRNA
Molecular chains
Neoplasm Metastasis
Neoplasm Transplantation
nuclear receptor
Prostate cancer
Proto-Oncogene Proteins c-met - genetics
Receptors, Steroid - genetics
Receptors, Steroid - metabolism
Receptors, Thyroid Hormone - genetics
Receptors, Thyroid Hormone - metabolism
renal cell carcinoma
Signal Transduction - drug effects
Sunitinib - pharmacology
TR4
TR4 protein
Transcription
Tumors
Up-Regulation - drug effects
Xenografts
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. What's new? About one‐third of patients with clear cell renal cell carcinoma (ccRCC) develop metastatic lesions, though the mechanisms behind this process are unclear. In this study, the transcriptional factor testicular nuclear receptor 4 (TR4) is identified as a potential promoter of ccRCC metastasis. Elevated TR4 expression was associated with metastasis in ccRCC cells and in clinical samples from ccRCC patients. In vitro, TR4 promoted RCC cell invasion and migration via altered hepatocyte growth factor (HGF)/Met/MMP2‐MMP9 signaling. Metastasis was suppressed in vitro and in vivo by the small molecules TR4‐shRNA and miR‐32‐5p, a microRNA typically downregulated in ccRCC metastatic patients.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.31289