Liver X receptor agonists exert antitumor effects against hepatocellular carcinoma via inducing REPS2 expression

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Liver X receptor (LXR) agonists demonstrate significant antitumor potential against various cancer types, including hepatocellular carcinoma (HCC).
• The precise molecular mechanisms driving LXR's antitumor activity, particularly in HCC, remain incompletely elucidated.
• The RalA binding protein 1 (RALBP1)-associated EPS domain containing 2 (REPS2)/epidermal growth factor receptor (EGFR) signaling axis is implicated in cancer progression.

Purpose of the Study:

• To investigate the impact of the LXR agonist T0901317 (T317) on hepatocellular carcinoma (HCC) development.
• To elucidate the relationship between T317, REPS2 expression, and the REPS2/EGFR signaling pathway in HCC.
• To explore the potential of REPS2 as a therapeutic target in HCC.

Main Methods:

• Dose-dependent treatment of normal hepatocytes and HCC cell lines with T317.
• Analysis of REPS2 expression using quantitative PCR and Western blotting.
• Promoter activity assays and chromatin immunoprecipitation (CHIP) to assess transcriptional regulation of REPS2 by LXR.
• Assessment of HCC cell proliferation and migration.
• Investigation of EGFR endocytosis and downstream signaling pathways (AKT/NF-κB, p38MAPK, ERK1/2) following T317 treatment.
• Correlation analysis of REPS2 expression with clinical HCC data and patient prognosis.

Main Results:

• T317 significantly and dose-dependently increased REPS2 expression at the transcriptional level in both normal and HCC cells.
• T317 treatment inhibited HCC cell proliferation and migration, effects closely linked to elevated REPS2 levels.
• T317 suppressed EGF-mediated EGFR endocytosis and attenuated downstream signaling pathways, including AKT/NF-κB, p38MAPK, and ERK1/2.
• Clinical data indicated an inverse correlation between REPS2 expression and HCC development, with reduced REPS2 associated with poor prognosis.

Conclusions:

• This study demonstrates that the LXR agonist T317 enhances REPS2 expression transcriptionally, thereby inhibiting HCC cell proliferation and migration.
• T317 exerts its antitumor effects by modulating the REPS2/EGFR axis, specifically by inhibiting EGFR endocytosis and downstream signaling.
• REPS2 represents a potential tumor suppressor in HCC, and its regulation by LXR agonists offers novel therapeutic insights for liver cancer treatment.