title: Cooperative interaction of MUC1 with the HGF/c-Met pathway during hepatocarcinogenesis.
abstract: BACKGROUND
  Hepatocyte growth factor (HGF) induced c-Met activation is known as the main stimulus for hepatocyte proliferation and is essential for liver development and regeneration. Activation of HGF/c-Met signaling has been correlated with aggressive phenotype and poor prognosis in hepatocellular carcinoma (HCC). MUC1 is a transmembrane mucin, whose over-expression is reported in most cancers. Many of the oncogenic effects of MUC1 are believed to occur through the interaction of MUC1 with signaling molecules. To clarify the role of MUC1 in HGF/c-Met signaling, we determined whether MUC1 and c-Met interact cooperatively and what their role(s) is in hepatocarcinogenesis.
  
  
  RESULTS
  MUC1 and c-Met over-expression levels were determined in highly motile and invasive, mesenchymal-like HCC cell lines, and in serial sections of cirrhotic and HCC tissues, and these levels were compared to those in normal liver tissues. Co-expression of both c-Met and MUC1 was found to be associated with the differentiation status of HCC. We further demonstrated an interaction between c-Met and MUC1 in HCC cells. HGF-induced c-Met phosphorylation decreased this interaction, and down-regulated MUC1 expression. Inhibition of c-Met activation restored HGF-mediated MUC1 down-regulation, and decreased the migratory and invasive abilities of HCC cells via inhibition of β-catenin activation and c-Myc expression. In contrast, siRNA silencing of MUC1 increased HGF-induced c-Met activation and HGF-induced cell motility and invasion.
  
  
  CONCLUSIONS
  These findings indicate that the crosstalk between MUC1 and c-Met in HCC could provide an advantage for invasion to HCC cells through the β-catenin/c-Myc pathway. Thus, MUC1 and c-Met could serve as potential therapeutic targets in HCC.
authors.affiliation: Department of Medical Biology and Genetics, Dokuz Eylul University, Medical School, Balcova-Izmir, Turkey.
authors.forename: Giray
authors.initials: G
authors.lastname: Bozkaya
authors.forename: Peyda
authors.initials: P
authors.lastname: Korhan
authors.forename: Murat
authors.initials: M
authors.lastname: Cokaklı
authors.forename: Esra
authors.initials: E
authors.lastname: Erdal
authors.forename: Ozgül
authors.initials: O
authors.lastname: Sağol
authors.forename: Sedat
authors.initials: S
authors.lastname: Karademir
authors.forename: Christopher
authors.initials: C
authors.lastname: Korch
authors.forename: Neşe
authors.initials: N
authors.lastname: Atabey
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D007211:Indoles; D018396:Mucin-1; D010879:Piperazines; D016271:Proto-Oncogene Proteins c-myc; D013449:Sulfonamides; D051176:beta Catenin; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met