ING4 suppresses hepatocellular carcinoma via a NF-κB/miR-155/FOXO3a signaling axis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• The tumor suppressor ING4 is frequently reduced in human hepatocellular carcinoma (HCC), and its alteration is linked to HCC progression.
• The precise role and underlying mechanisms of ING4 in HCC remain largely undefined.

Purpose of the Study:

• To investigate the functional impact of ING4 on HCC progression and elucidate its molecular mechanisms.
• To explore the potential of ING4 as a therapeutic target for HCC treatment.

Main Methods:

• Analysis of ING4 expression in HCC tissues and correlation with clinical parameters.
• Overexpression and knockdown of ING4 in human HCC cell lines (MHCC97H and MHCC97L).
• In vitro assays for cell proliferation, migration, invasion, cell cycle, and apoptosis.
• In vivo metastasis models in athymic nude mice.
• Mechanistic studies involving gene expression analysis (mRNA and protein), transcriptional activity assays, and regulatory pathway analysis (NF-κB, miR-155, FOXO3a).

Main Results:

• Downregulation of ING4 in HCC tissues correlated with advanced cancer staging, larger tumor size, and vascular invasion.
• ING4 overexpression suppressed HCC cell proliferation, migration, invasion, induced G1 cell cycle arrest, and apoptosis in vitro.
• ING4 overexpression inhibited tumor growth and lung metastasis in vivo.
• ING4 upregulated FOXO3a expression and activity, repressed NF-κB transcriptional activity, and decreased miR-155 expression.
• Knockdown of FOXO3a abrogated ING4's tumor-suppressive effects.
• The NF-κB/miR-155/FOXO3a pathway was identified as crucial for ING4's tumor-inhibitory function.

Conclusions:

• ING4 acts as a suppressor of human HCC growth and metastasis.
• ING4 exerts its tumor-inhibitory effects through the NF-κB/miR-155/FOXO3a signaling pathway.
• Restoring ING4 expression or targeting this pathway may represent a novel therapeutic strategy for HCC.