INCREASED LEVELS OF INSULIN-LIKE-GROWTH-FACTOR-II (IGF-II) AND IGF-BINDING PROTEIN-2 ARE ASSOCIATED WITH MALIGNANCY IN SPORADIC ADRENOCORTICAL TUMORS

In adrenocortical tumors, malignancy is strongly associated with insul in-like growth factor II (IGF-II) gene overexpression and abnormalitie s at the 11p15 locus, suggesting a role for this growth factor in adre nocortical tumorigenesis. To further investigate this role, the IGF/IG F-binding protein (IGFBP) system was analyzed in 18 adrenocortical tum ors, classified into 2 groups on the basis of their TGF-II messenger r ibonucleic acid (mRNA) content (group 1, normal IGF-II mRNA content, m ostly benign tumors; group 2, high IGF-II mRNA content, mostly maligna nt tumors). Group 2 tumors contained 10 times more IGF-II protein than group 1 tumors or normal adrenal tissue (P < 0.001), indicating effic ient translation of IGF-II mRNA in malignant tumors. Western ligand bl otting detected various functional IGFBPs in normal adrenocortical gla nds and tumors: a doublet of 39-42 kDa identified by immunoblotting as IGFBP-3, a band at 32 kDa, and bands at 29-30 and 24 kDa. Total IGFBP -3 protein levels were similar in the two groups of tumors. By contras t, malignant tumors differed from benign ones by specific expression o f the 32-kDa IGFBP. Immunoblotting identified this 32-kDa band togethe r with a proteolytic fragment of 25 kDa as IGFBP-2, and quantitative a nalysis showed significantly higher levels of total IGFBP-2 in maligna nt tumors than in benign tumors (P < 0.001). Despite enhanced levels o f IGBP-2 protein in malignant tumors, no increase in IGFBP-2 mRNA leve ls was detected, suggesting post-transcriptional regulation of this IG FBP. These results confirm the major role of IGF-II in adrenocortical tumorigenesis and suggest that IGFBP-2 maybe a regulator of IGF-II pro liferative effects in this tumor system.