High expression of insulin‐like growth factor binding protein‐3 is correlated with lower portal invasion and better prognosis in human hepatocellular carcinoma

Insulin‐like growth factor binding protein‐3 (IGFBP‐3) modulates cell proliferation of various cancer cell types. However, it remains unclear how IGF–IGFBP‐3‐signaling is involved in growth and progression of hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the role of IGFBP‐3 in HCC. Type 1 receptor for IGF (IGF‐1R) was expressed at various levels in the seven lines examined, but IGF‐2R was not expressed. Of the seven lines, the growth of HAK‐1B, KIM‐1, KYN‐2 and HepG2 cells was stimulated in a dose‐dependent manner by the exogenous addition of IGF‐I or IGF‐II, but the HAK‐1A, KYN‐1 and KYN‐3 cell lines showed no growth. Exogenous addition of IGFBP‐3 markedly blocked IGF‐I and IGF‐II‐stimulated cell growth of KYN‐2 and HepG2 cells, and moderately stimulated that of KIM‐1 and HAK‐1B cells, but no growth of the KYN‐1, KYN‐3 and HAK‐1A cell lines was observed. IGF‐I enhanced the phosphorylation of IGF‐1R, Akt and Erk1/2 in KYN‐2 cells, and coadministration of IGFBP‐3 blocked all types of activation by IGF‐I investigated here. In contrast, no such activation by IGF‐I was detected in KYN‐3 cells. IGFBP‐3 also suppressed IGF‐I‐induced cell invasion by KYN‐2 cells. Moreover, we were able to observe the apparent expression of IGFBP‐3 in KYN‐3 cells, but not in the other six cell lines. Furthermore reduced expression of IGFBP‐3, but not that of IGF‐1R, was significantly correlated with tumor size, histological differentiation, capsular invasion and portal venous invasion. Low expression of IGFBP‐3 was independently associated with poor survival. IGFBP‐3 could be a molecular target of intrinsic importance for further development of novel therapeutic strategy against HCC. (Cancer Sci 2006; 97: 1182–1190)