title: TR4 nuclear receptor enhances the cisplatin chemo-sensitivity via altering the ATF3 expression to better suppress HCC cell growth.
abstract: 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.
authors.affiliation: Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.|George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Jiliang
authors.initials: J
authors.lastname: Shen
authors.affiliation: Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Lin
authors.affiliation: Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
authors.forename: Gonghui
authors.initials: G
authors.lastname: Li
authors.affiliation: Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.|George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Ren-An
authors.initials: RA
authors.lastname: Jin
authors.affiliation: Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.|George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Shi
authors.affiliation: Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Chen
authors.affiliation: George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.|Sex Hormone Research Center, China Medical University/Hospital, Taichung 404, Taiwan.
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
authors.affiliation: Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
authors.forename: Xiujun
authors.initials: X
authors.lastname: Cai
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008819:Mice, Nude; D034622:RNA Interference; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D000970:Antineoplastic Agents; C490515:NR2C2 protein, human; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D002945:Cisplatin
keywords: ATF3; TR4; TR4 response element; chemotherapy; hepatocellular carcinoma