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

Area of Science:

• Oncology
• Molecular Biology
• Hepatology

Background:

• The role of the TR4 nuclear receptor (TR4) in prostate cancer is established, but its involvement in liver cancer progression is unclear.
• Hepatocellular carcinoma (HCC) is a major global health concern, and improving chemotherapy response is critical.

Purpose of the Study:

• To investigate the role of TR4 in hepatocellular carcinoma (HCC) progression and its impact on cisplatin chemotherapy efficacy.
• To elucidate the molecular mechanisms by which TR4 influences HCC response to cisplatin.

Main Methods:

• Utilized HCC cell lines (Huh7, Hep3B, LM3, SNU387) with TR4 knockdown (TR4-siRNA) and overexpression (TR4-cDNA).
• Assessed cisplatin chemotherapy sensitivity and resistance in vitro.
• Investigated the role of ATF3 expression at the transcriptional level and used ATF3-siRNA to interrupt its function.
• Validated findings in an in vivo HCC mouse model using xenografted HCC LM3 cells.

Main Results:

• Higher TR4 expression in HCC cells enhanced cisplatin chemotherapy efficacy.
• TR4 knockdown increased cisplatin resistance, while TR4 overexpression increased sensitivity.
• TR4 modulated ATF3 expression transcriptionally, and this interaction was crucial for enhancing cisplatin sensitivity.
• Interrupting ATF3 expression reversed the pro-sensitivity effects of TR4.
• In vivo studies confirmed that TR4 enhances cisplatin chemotherapy sensitivity in HCC.

Conclusions:

• TR4 nuclear receptor plays a significant role in enhancing cisplatin chemotherapy sensitivity in hepatocellular carcinoma.
• The TR4-ATF3 signaling pathway is a key mechanism mediating this effect.
• Targeting the TR4-ATF3 axis presents a potential therapeutic strategy to improve cisplatin efficacy for HCC treatment.