title: IGFBP-4 activates the Wnt/beta-catenin signaling pathway and induces M-CAM expression in human renal cell carcinoma.
abstract: The Wnt/β-catenin signaling pathway is inactivated by Wnt antagonists in most cancers and IGFBP-4 is an antagonist of the Wnt/ β-catenin signaling pathway. However, the function of IGFBP-4 is not currently understood in renal cell carcinoma (RCC). We initially found that the expression of IGFBP-4 was significantly lower in primary RCC and higher in metastatic RCC compared to normal human kidney tissues. To assess the function of IGFBP4, we established IGFBP4 transfectants (primary renal cancer cell line) and performed functional analyses including Tcf reporter assays, cell viability, invasive capability, mortality, and in vivo tumor growth. Interestingly IGFBP-4 transfectants promoted cell growth (in vitro and in vivo), invasion, and motility in primary renal cancer. Tcf transcriptional activity was significantly increased in IGFBP-4 transfectants compared to mock cells and β-catenin expression was increased. Also the β-catenin downstream effector, MT1-MMP showed increased expression in IGFBP4 transfectants. Additionally IGFBP4 induced the expression of M-CAM, a marker of tumor progression. In order to assess the role of IGFBP4 in metastatic renal cancer, IGFBP-4 mRNA in a metastatic renal cancer cell lines (ACHN) was knocked-down using a siRNA technique. The cell growth and motility was decreased in si-IGFBP4 transfected ACHN cells compared to cells transfected with control siRNA. Tcf activity in ACHN cells was also decreased with si-IGFBP-4 transfection. This is a first report documenting that IGFBP-4 expression in RCC activates cell growth, metastasis, Wnt/beta-catenin signaling and may be involved in RCC metastasis.
authors.affiliation: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, CA94121, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Ueno
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirata
authors.forename: Shahana
authors.initials: S
authors.lastname: Majid
authors.forename: Z Laura
authors.initials: ZL
authors.lastname: Tabatabai
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hinoda
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
mesh_terms: D051929:CD146 Antigen / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D055785:Gene Knockdown Techniques; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051929:CD146 Antigen; D018974:Insulin-Like Growth Factor Binding Protein 4; C497902:MCAM protein, human; D051153:Wnt Proteins; D051176:beta Catenin