IGFBP2 upregulates ZEB1 expression and promotes hepatocellular carcinoma progression through NF-κB signaling pathway

Hepatocellular carcinoma (HCC) is one of the most lethal cancers owing to the high metastasis rate. The molecular mechanism underlying HCC progression remains unclear.

We aimed to explore the function and mechanism of action of insulin-like growth factor binding protein 2 (IGFBP2) in HCC.

Expression of IGFBP2 was evaluated with western blotting and reverse transcription polymerase chain reaction (RT-PCR). Loss- and gain-function assays were conducted to evaluate the effects of IGFBP2 on HCC cell proliferation, migration, and invasion. Signaling pathways were screened with a dual-fluorescein reporting system, and levels of epithelial and mesenchymal markers were measured after altering IGFBP2 expression. Cell fractionation analysis was conducted to evaluate the nuclear translocation of p65.

IGFBP2 expression was upregulated in HCC tissues, predicted worse prognosis, and was associated with strong metastatic potentials. IGFBP2 depletion significantly inhibited HCC cell proliferation, migration, and invasion, whereas IGFBP2 overexpression showed reverse phenotypes. The underlying mechanism involved IGFBP2-mediated nuclear localization of p65, which activated nuclear factor kappa B (NF-κB) and zinc finger E-Box binding homeobox 1 (ZEB1) transcription via binding to the gene promoter.

This study for the first time identifies IGFBP2 as a novel therapeutic target in HCC that activates the NF-κB-ZEB1 signaling axis and promotes HCC tumorigenesis.