TR4 nuclear receptor promotes prostate cancer metastasis via upregulation of CCL2/CCR2 signaling
Authors: Gonghui Li
Xianfan Ding
Chawnshang Chang
Yuan-Jie Niu
Liqun Xia
Dong-Rong Yang
Shicheng Yu
Shin-Jen Lin
Soo Ok Lee
Ya-Ling Chen
Journal: International journal of cancer (2015)
Discipline: CLINICAL MEDICINE
Keywords: CCL2/CCR2; TR4; metastasis; prostate cancer.
Affiliations: Chawnshang Chang Liver Cancer Center, Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejang University, Hangzhou, China; George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY., George Whipple Lab for Cancer Research; Departments of Pathology; Urology; and Radiation Oncology; and The Wilmot Cancer Center; University of Rochester Medical Center; Rochester NY, Department of Urology; The Second Affiliated Hospital of Soochow University; Suzhou China, Chawnshang Chang Liver Cancer Center; Department of Urology; Sir Run Run Shaw Hospital; School of Medicine, Zhejang University; Hangzhou China, Chawnshang Chang Sex Hormone Research Center; Department of Urology; The Second Hospital of Tianjin Medical University; Tianjin China, Sex Hormone Research Center; China Medical University/Hospital; Taichung Taiwan

Abstract:  Testicular nuclear receptor 4 (TR4) plays protective roles against oxidative stress and DNA damage and might contribute to aging. Our recent clinical tumor tissue staining results showed higher expression of TR4 in prostate cancer (PCa) patients with high Gleason scores compared to the tissues with the low Gleason scores. In vitro migration/invasion assays after manipulation of the TR4 expression in PCa cells showed that TR4 promoted PCa cells migration/invasion. Mechanism dissection found that the CCL2/CCR2 signal plays the key role in the mediation of TR4-promoted PCa cells migration/invasion. Chromatin immunoprecipitation and Luciferase assays further confirmed TR4 modulation of CCL2 at the transcriptional level and addition of the CCR2 antagonist led to interruption of the TR4-enhanced PCa cells migration/invasion. Finally, the orthotopic xenografted mice studies using the luciferase expressing CWR22Rv1 cells found that TR4 enhanced PCa metastasis and this increased metastasis was reversed when the CCR2 antagonist was injected into the mice. Together, these in vitro and in vivo results revealed a positive role of TR4 in PCa metastasis and demonstrated CCL2/CCR2 signaling as an important mediator in exerting TR4 action. This finding suggests that TR4 may represent a biomarker related to PCa metastasis and targeting the TR4-CCL2/CCR2 axis may become a new therapeutic approach to battle PCa metastasis. 

Retracted: No

PubPeer comments:
 Figure 3B and 5B: * Red boxes: Two panels appear to look very similar to each other. One shows migration, the other invasion. Could the authors please check?  , 
 NIH; Grant number: CA156700 and DK73414 , 
 Erratum, August 2020: https: onlinelibrary.wiley.com doi 10.1002 ijc.33220  There are errors in images presented in Fig. 2b and Fig. 3b  The left microscopic image in Fig.5a (u201cvectoru201d) was accidentally reused in the left microscopic image in Fig.2b, (u201cscru201d). The middle microscopic image in Fig.5b in the right diagram (u201cTR4u201d) was inadvertently reused in the right microscopic image in Fig.3b (u201cTR4u201d). Due to an error while processing the figures the authors inserted the wrong images in Fig.2b and Fig.3b. The correct versions of the figures are presented below. The authors assure that these corrections do not change the original results and conclusions and apologize for the mistakes. ,