TR4 nuclear receptor enhances the cisplatin chemo-sensitivity via altering the ATF3 expression to better suppress HCC cell growth

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.