Insulin-like growth factor-binding protein-3 inhibits IGF-1-induced proliferation of human hepatocellular carcinoma cells / 中国药理学与毒理学杂志

ABSTRACT

OBJECTIVE Basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) produced by hepatocellular carcinoma (HCC) cells are responsible for the cell growth. Accumu?lating evidence shows that insulin-like growth factor-binding protein-3 (IGFBP-3) suppresses HCC cell proliferation in both IGF- dependent and independent manners. The present study is to investigate whether treatment with exogenous IGFBP-3 inhibits bFGF and PDGF production and the cell proliferation of HCC cells. METHODS Cell Counting Kit 8 assay were designed to detect HCC cell proliferation, transcription factor early growth response- 1 (EGR1) involving in IGFBP- 3 regulation of bFGF and PDGF were detected by RT-PCR and Western blot assays. Western blot assay was adopted to detect the IGFBP- 3 regulating insulin- like growth factor 1 receptor (IGF- 1R) signaling pathway. RESULTS The present study demonstrates that IGFBP-3 suppressed IGF-1-induced bFGF and PDGF expression while it does not affect their expression in the absence of IGF-1. To delineate the underlying mechanism, Western-blot and RT-PCR assays confirmed that the transcription factor early growth response protein 1 (EGR1) is involved in IGFBP-3 regulation of bFGF and PDGF. IGFBP-3 inhibition of type 1 insulin-like growth factor receptor (IGF1R), ERK and AKT activation is IGF- 1- dependent. Furthermore, transient transfection with constitutively activated AKT or MEK partially blocks the IGFBP-3 inhibition of EGR1, bFGF and PDGF expression. CONCLUSION In conclusion, these findings suggest that IGFBP- 3 suppresses transcription of EGR1 and its target genes bFGF and PDGF through inhibiting IGF- 1-dependent ERK and AKT activation. It demonstrates the importance of IGFBP-3 in the regulation of HCC cell proliferation, suggesting that IGFBP-3 could be a target for the treatment of HCC.