title: Connective tissue growth factor autocriny in human hepatocellular carcinoma: oncogenic role and regulation by epidermal growth factor receptor/yes-associated protein-mediated activation.
abstract: The identification of molecular mechanisms involved in the maintenance of the transformed phenotype of hepatocellular carcinoma (HCC) cells is essential for the elucidation of therapeutic strategies. Here, we show that human HCC cells display an autocrine loop mediated by connective tissue growth factor (CTGF) that promotes DNA synthesis and cell survival. Expression of CTGF was stimulated by epidermal growth factor receptor (EGFR) ligands and was dependent on the expression of the transcriptional coactivator, Yes-associated protein (YAP). We identified elements in the CTGF gene proximal promoter that bound YAP-enclosing complexes and were responsible for basal and EGFR-stimulated CTGF expression. We also demonstrate that YAP expression can be up-regulated through EGFR activation not only in HCC cells, but also in primary human hepatocytes. CTGF contributed to HCC cell dedifferentiation, expression of inflammation-related genes involved in carcinogenesis, resistance toward doxorubicin, and in vivo HCC cell growth. Importantly, CTGF down-regulated tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 expression and was involved in the reduced sensitivity of these cells toward TRAIL-mediated apoptosis.
  
  
  CONCLUSIONS
  We have identified autocrine CTGF as a novel determinant of HCC cells' neoplastic behavior. Expression of CTGF can be stimulated through the EGFR-signaling system in HCC cells in a novel cross-talk with the oncoprotein YAP. Moreover, to our knowledge, this is the first study that identifies a signaling mechanism triggering YAP gene expression in healthy and transformed liver parenchymal cells.
authors.affiliation: Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Urtasun
authors.forename: Maria U
authors.initials: MU
authors.lastname: Latasa
authors.forename: Maria I
authors.initials: MI
authors.lastname: Demartis
authors.forename: Stella
authors.initials: S
authors.lastname: Balzani
authors.forename: Saioa
authors.initials: S
authors.lastname: Goñi
authors.forename: Oihane
authors.initials: O
authors.lastname: Garcia-Irigoyen
authors.forename: Maria
authors.initials: M
authors.lastname: Elizalde
authors.forename: Maria
authors.initials: M
authors.lastname: Azcona
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Pascale
authors.forename: Francesco
authors.initials: F
authors.lastname: Feo
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.forename: Charles
authors.initials: C
authors.lastname: Balabaud
authors.forename: Jordi
authors.initials: J
authors.lastname: Muntané
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
authors.forename: Carmen
authors.initials: C
authors.lastname: Berasain
authors.forename: Matias A
authors.initials: MA
authors.lastname: Avila
mesh_terms: D019898:Autocrine Communication / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology*; D018797:Cell Cycle Proteins; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000502:physiology*; D061251:Primary Cell Culture; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D055513:Connective Tissue Growth Factor; D004317:Doxorubicin; D066246:ErbB Receptors