TR4 nuclear receptor enhances the cisplatin chemo-sensitivity via altering the ATF3 expression to better suppress HCC cell growth
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Jiliang Shen1,2,*, Hui Lin1,*, Gonghui Li1,*, Ren-An Jin1,2, Liang Shi1,2, Mingming Chen1, Chawnshang Chang2,3, Xiujun Cai1
1Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China
2George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA
3Sex Hormone Research Center, China Medical University/Hospital, Taichung 404, Taiwan
*These authors contributed equally to this work
Xiujun Cai, email: [email protected]
Chawnshang Chang, email: [email protected]
Keywords: TR4, hepatocellular carcinoma, chemotherapy, TR4 response element, ATF3
Received: September 02, 2015 Accepted: March 02, 2016 Published: April 01, 2016
Early studies indicated that TR4 nuclear receptor (TR4) may play a key role to modulate the prostate cancer progression, its potential linkage to liver cancer progression, however, remains unclear. Here we found that higher TR4 expression in hepatocellular carcinoma (HCC) cells might enhance the efficacy of cisplatin chemotherapy to better suppress the HCC progression. Knocking down TR4 with TR4-siRNA in HCC Huh7 and Hep3B cells increased cisplatin chemotherapy resistance and overexpression of TR4 with TR4-cDNA in HCC LM3 and SNU387 cells increased cisplatin chemotherapy sensitivity. Mechanism dissection found that TR4 might function through altering the ATF3 expression at the transcriptional level to enhance the cisplatin chemotherapy sensitivity, and interrupting ATF3 expression via ATF3-siRNA reversed TR4-enhanced cisplatin chemotherapy sensitivity in HCC cells. The in vivo HCC mouse model using xenografted HCC LM3 cells also confirmed in vitro cell lines data showing TR4 enhanced the cisplatin chemotherapy sensitivity. Together, these results provided a new potential therapeutic approach via altering the TR4-ATF3 signals to increase the efficacy of cisplatin to better suppress the HCC progression.
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