IGFBP-3 expression in hepatocellular carcinoma involves abnormalities in TGF-beta and/or Rb signaling pathways.
Insulin-like growth factor binding protein-3 (IGFBP-3) is a mediator of growth suppression signals and a putative tumor suppressor gene. The growth suppression mechanisms of IGFBP-3 have not been well clarified. We examined the expression of IGFBP-3 transcripts in human hepatocellular carcinoma (HCC) and the relationship between IGFBP-3 expression and the transforming growth factor-beta (TGF-beta) and/or retinoblastoma (Rb) signaling pathways. In situ hybridization revealed IGFBP-3 transcripts in cancer cells in 6 of 57 (10%) HCCs, including moderately and poorly differentiated HCCs with intrahepatic metastasis. In contrast, all lung metastatic nodules of 4 HCCs showed IGFBP-3 transcripts in cancer cells. The cDNA microarray showed that genes for the TGF-beta pathway and Rb were up-regulated in IGFBP-3-expressing HCCs. In 6 HCCs presenting IGFBP-3, immunohistochemical analyses showed abnormalities in the TGF-beta and/or Rb pathways; the loss of phosphorylated-Smad2 was observed in 2, and overexpression of phosphorylated-Rb was observed in the remaining 4 HCCs. The present study suggests that IGFBP-3 mediates growth suppression signals via the TGF-beta and/or Rb pathways in HCC.
Yumoto
Eiichiro
E
Department of Medicine, Okayama University Graduate School of Medicine and Dentistry, Japan. yumoto-gi@umin.ac.jp
Nakatsukasa
Harushige
H
Hanafusa
Tadashi
T
Yumoto
Yasuhiro
Y
Nouso
Kazuhiro
K
Matsumoto
Eiji
E
Onishi
Toru
T
Takuma
Yoshitaka
Y
Tanaka
Hironori
H
Fujikawa
Tatsuya
T
Suzuki
Mayumi
M
Uemura
Masayuki
M
Shiratori
Yasushi
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002454:Cell Differentiation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000096:biosynthesis* / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016160:Retinoblastoma Protein / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D018972:Insulin-Like Growth Factor Binding Protein 3; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta