title: Late SV40 factor (LSF) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP-9).
abstract: The transcription factor late SV40 factor (LSF) is overexpressed in human hepatocellular carcinoma (HCC) fostering a highly aggressive and metastatic phenotype. Angiogenesis is an essential component of cancer aggression and metastasis and HCC is a highly aggressive and angiogenic cancer. In the present studies, we analyzed the molecular mechanism of LSF-induced angiogenesis in HCC. Employing human umbilical vein endothelial cells (HUVEC) differentiation assay and chicken chorioallantoic membrane (CAM) assay we document that stable LSF overexpression augments and stable dominant negative inhibition of LSF (LSFdn) abrogates angiogenesis by human HCC cells. A quest for LSF-regulated factors contributing to angiogenesis, by chromatin immunoprecipitation-on-chip (ChIP-on-chip) assay, identified matrix metalloproteinase-9 (MMP-9) as a direct target of LSF. MMP-9 expression and enzymatic activity were higher in LSF-overexpressing cells and lower in LSFdn-expressing cells. Deletion mutation analysis identified the LSF-responsive regions in the MMP-9 promoter and ChIP assay confirmed LSF binding to the MMP-9 promoter. Inhibition of MMP-9 significantly abrogated LSF-induced angiogenesis as well as in vivo tumorigenesis, thus reinforcing the role of MMP-9 in facilitating LSF function. The present findings identify a novel target of LSF contributing to its oncogenic properties.
authors.affiliation: Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors.forename: Prasanna K
authors.initials: PK
authors.lastname: Santhekadur
authors.forename: Rachel
authors.initials: R
authors.lastname: Gredler
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Ayesha
authors.initials: A
authors.lastname: Siddiq
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Shen
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000451:nursing; D045744:Cell Line, Tumor; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics; D020218:Response Elements; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C501906:TFCP2 protein, human; D014157:Transcription Factors; D020780:Matrix Metalloproteinase 9