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World J Gastroenterol. Oct 28, 2006; 12(40): 6531-6535
Published online Oct 28, 2006. doi: 10.3748/wjg.v12.i40.6531
Signaling pathway of insulin-like growth factor-II as a target of molecular therapy for hepatoblastoma
Minoru Tomizawa, Hiromitsu Saisho
Minoru Tomizawa, Hiromitsu Saisho, Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8670, Japan
Supported by the Japan Society for the Promotion of Science (JSPS) (16590577) and the Kawano Masanori Memorial Foundation for Promotion of Pediatrics (15-6)
Correspondence to: Minoru Tomizawa, Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8670, Japan. nihminor-cib@umin.ac.jp
Telephone: +81-43-2262083 Fax: +81-43-2262088
Received: July 19, 2006
Revised: August 12, 2006
Accepted: September 11, 2006
Published online: October 28, 2006
Abstract

AIM: To address the possibility that insulin-like growth factor (IGF)-II is a growth factor and its signaling pathway so as to develop a molecular therapy for hepatoblastoma.

METHODS: Huh-6 and HepG2, human hepatoblastoma cell lines, were used. IGF-II was added to the medium deprived of serum. Western blot analysis was performed to clarify the expression of IGF-I receptor (IGF-IR). Inhibitors of IGF-IR (picropodophyllin, PPP), phosphatidyl-inositol (PI) 3-kinase (LY294002 and Wortmannin), or mitogen-activated protein (MAP) kinase (PD98059) were added to unveil the signaling pathway of IGF-II. Cells were analyzed morphologically with hematoxylin-eosin staining to reveal the mechanism of suppression of cell proliferation.

RESULTS: IGF-II stimulated cells proliferated to 2.7 (269% ± 76%) (mean ± SD) (Huh-6) and 2.1 (211% ± 85%) times (HepG2). IGF-IR was expressed in Huh-6 and HepG2. PPP suppressed the cell number to 44% ± 11% (Huh-6) and 39% ± 5% (HepG2). LY294002 and Wortmannin suppressed the cell number to 30% ± 5% (Huh-6), 44% ± 0.4% (HepG2), 49% ± 1.0% (Huh-6) and 46% ± 1.1% (HepG2), respectively. PD98059 suppressed the cell number to 33% ± 11% for HepG2 but not for Huh-6. When cell proliferation was prohibited, many Huh-6 and HepG2 cells were dead with pyknotic or fragmented nuclei, suggesting apoptosis.

CONCLUSION: IGF-II was shown to be a growth factor of hepatoblastoma via IGF-I receptor and PI3 kinase which were good candidates for target of molecular therapy.

Keywords: 3- (4, 5-dimethylthiazol-2-yl)-5- (3-carboxymethoxyphenyl)-2- (4-sulfophenyl) -2H-tetrazolium inner salt assay; Phosphatidyl-inositol-3-kinase; Mitogen-activated protein kinase; Hepatoblastoma; Molecular therapy