title: c-Met activation through a novel pathway involving osteopontin mediates oncogenesis by the transcription factor LSF.
abstract: OBJECTIVE
  Understanding the molecular pathogenesis of hepatocellular carcinoma (HCC) would facilitate development of targeted and effective therapies for this fatal disease. We recently demonstrated that the cellular transcription factor Late SV40 Factor (LSF) is overexpressed in more than 90% of human HCC cases, compared to the normal liver, and plays a seminal role in hepatocarcinogenesis. LSF transcriptionally upregulates osteopontin (OPN) that plays a significant role in mediating the oncogenic function of LSF. The present study aims at a better understanding of LSF function by analyzing the signaling pathway modulated by LSF.
  
  
  METHODS
  Phospho-receptor tyrosine kinase (RTK) array was performed to identify which receptor tyrosine kinases are activated by LSF. Immunohistochemical analysis using tissue microarray was performed to establish correlation among LSF, OPN, and phospho-c-Met levels in HCC patients. Co-immunoprecipitation analysis was performed to check OPN-induced CD44 and c-Met interaction. Inhibition studies using chemicals and siRNAs were performed in vitro and in vivo using nude mice xenograft models to establish the importance of c-Met activation in mediating LSF function.
  
  
  RESULTS
  Secreted OPN, induced by LSF, activates c-Met via a potential interaction between OPN and its cell surface receptor CD44. A significant correlation was observed among LSF, OPN, and activated c-Met levels in HCC patients. Chemical or genetic inhibition of c-Met resulted in profound abrogation of LSF-mediated tumorigenesis and metastasis in nude mice xenograft studies.
  
  
  CONCLUSIONS
  The present findings elucidate a novel pathway of c-Met activation during hepatocarcinogenesis and support the rationale of using c-Met inhibitors as potential HCC therapeutics.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
authors.forename: Byoung Kwon
authors.initials: BK
authors.lastname: Yoo
authors.forename: Rachel
authors.initials: R
authors.lastname: Gredler
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Prasanna K
authors.initials: PK
authors.lastname: Santhekadur
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 / Q000209:etiology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D053495:Osteopontin / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: C497483:CD44 protein, human; D004268:DNA-Binding Proteins; D018960:Hyaluronan Receptors; C501906:TFCP2 protein, human; D014157:Transcription Factors; D053495:Osteopontin; D019859:Proto-Oncogene Proteins c-met