Biological effects induced by insulin-like growth factor binding protein 3 (IGFBP-3) in malignant melanoma.
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.
Oy
Geir Frode
GF
Department of Tumor Biology, Institute for Cancer Research, Oslo, Norway.
Slipicevic
Ana
A
Davidson
Ben
B
Solberg Faye
Ragnar
R
Maelandsmo
Gunhild M
GM
Flørenes
Vivi Ann
VA
D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics* / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D018972:Insulin-Like Growth Factor Binding Protein 3; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3