title: High expression of insulin-like growth factor binding protein-3 is correlated with lower portal invasion and better prognosis in human hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Aishima
authors.forename: Yuji
authors.initials: Y
authors.lastname: Basaki
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Kuroda
authors.forename: Yunosuke
authors.initials: Y
authors.lastname: Nishihara
authors.forename: Kenichi
authors.initials: K
authors.lastname: Taguchi
authors.forename: Akinobu
authors.initials: A
authors.lastname: Taketomi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
authors.forename: Fumihito
authors.initials: F
authors.lastname: Hosoi
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Maruyama
authors.forename: Abbas
authors.initials: A
authors.lastname: Fotovati
authors.forename: Shinji
authors.initials: S
authors.lastname: Oie
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
authors.forename: Takato
authors.initials: T
authors.lastname: Ueno
authors.forename: Michio
authors.initials: M
authors.lastname: Sata
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yano
authors.forename: Masamichi
authors.initials: M
authors.lastname: Kojiro
authors.forename: Michihiko
authors.initials: M
authors.lastname: Kuwano
authors.forename: Masazumi
authors.initials: M
authors.lastname: Tsuneyoshi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology*; D011169:Portal Vein / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D034741:RNA, Small Interfering; D007334:Insulin-Like Growth Factor I; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051057:Proto-Oncogene Proteins c-akt