Biological effects induced by insulin‐like growth factor binding protein 3 (IGFBP‐3) in malignant melanoma

Abstract

The insulin like growth factor (IGF) signaling pathway has been shown to contribute to melanoma progression, but little is known about the role of the IGF binding protein 3 (IGFBP‐3) in melanoma biology. The aim of the present study was to characterize expression, function and regulation of IGFBP‐3 in malignant melanomas and study its potential as a biomarker. The expression of IGFBP‐3 varied between different human melanoma cell lines and reintroduction of the protein in non‐expressing cells led to induction of apoptosis. Interestingly, in cell lines expressing endogenous IGFBP‐3, siRNA silencing of the protein led to a cell line‐dependent decrease in proliferation, but had no effect on apoptosis and invasion. Examination of patient material showed that IGFBP‐3 is unexpressed in benign nevi while a slight increase in protein expression was seen in primary and metastatic melanoma. However, expression of the protein was low and no correlation was found with circulating levels of IGFBP‐3 in serum, suggesting that IGFBP‐3 has limited potential as a predictive marker in malignant melanoma. We showed that promoter methylation of IGFBP‐3 occurred in both melanoma cell lines and patient material, implicating epigenetic silencing as a regulation mechanism. Furthermore, expression of the protein was shown to be regulated by the PI3‐kinase/AKT and MAPK/ERK1/2 pathways. In summary, our findings suggest that IGFBP‐3 can exert dual functional effects influencing both apoptosis and proliferation. Development of resistance to the antiproliferative effects of IGFBP‐3 may be an important step in progression of malignant melanomas.