Connective tissue growth factor autocriny in human hepatocellular carcinoma: Oncogenic role and regulation by epidermal growth factor receptor/yes-associated protein–mediated activation*

Authors

  • Raquel Urtasun,

    1. Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Pamplona, Spain
    Search for more papers by this author
    • *

      These authors contributed equally to this work.

  • Maria U. Latasa,

    1. Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Pamplona, Spain
    Search for more papers by this author
    • *

      These authors contributed equally to this work.

  • Maria I. Demartis,

    1. Division of Experimental Pathology and Oncology, Department of Clinical and Experimental Medicine and Oncology, University of Sassari, Sassari, Italy
    Search for more papers by this author
  • Stella Balzani,

    1. Division of Experimental Pathology and Oncology, Department of Clinical and Experimental Medicine and Oncology, University of Sassari, Sassari, Italy
    Search for more papers by this author
  • Saioa Goñi,

    1. Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Pamplona, Spain
    Search for more papers by this author
  • Oihane Garcia-Irigoyen,

    1. Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Pamplona, Spain
    Search for more papers by this author
  • Maria Elizalde,

    1. Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Pamplona, Spain
    Search for more papers by this author
  • Maria Azcona,

    1. Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Pamplona, Spain
    Search for more papers by this author
  • Rosa M. Pascale,

    1. Division of Experimental Pathology and Oncology, Department of Clinical and Experimental Medicine and Oncology, University of Sassari, Sassari, Italy
    Search for more papers by this author
  • Francesco Feo,

    1. Division of Experimental Pathology and Oncology, Department of Clinical and Experimental Medicine and Oncology, University of Sassari, Sassari, Italy
    Search for more papers by this author
  • Paulette Bioulac-Sage,

    1. Service d'Anatomie Pathologique, Hôpital Pellegrin, CHU Bordeaux, Bordeaux, France
    2. Service de Chirurgie Digestive, Hôpital Saint-André, CHU Bordeaux, Bordeaux, France
    Search for more papers by this author
  • Charles Balabaud,

    1. Service d'Anatomie Pathologique, Hôpital Pellegrin, CHU Bordeaux, Bordeaux, France
    2. Département d'Hepatologie, CHU Bordeaux, Bordeaux, France
    Search for more papers by this author
  • Jordi Muntané,

    1. Research Unit, CIBERehd, Reina Sofia University Hospital, Córdoba, Spain
    Search for more papers by this author
  • Jesus Prieto,

    1. Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Pamplona, Spain
    2. CIBERehd, University Clinic, University of Navarra, Pamplona, Spain
    Search for more papers by this author
  • Carmen Berasain,

    1. Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Pamplona, Spain
    Search for more papers by this author
    • These authors are senior coauthors.

  • Matias A. Avila

    Corresponding author
    1. Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Pamplona, Spain
    • Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
    Search for more papers by this author
    • These authors are senior coauthors.

    • fax: 34-948-194717; or Carmen Berasian, Ph.D., Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Avda Pio XII, n55, 31008, Pamplona, Spain. E-mail: cberasian@unav.es; fax: 34-948-194717


  • Potential conflict of interest: Nothing to report.

  • Work in the authors' laboratory is supported by the agreement between FIMA and the “UTE project CIMA.” Red Temática de Investigación Cooperativa en Cáncer RD06 00200061 (to C.B. and M.A.A.), CiberEhd (to J.P.), Fundación Echébano, Fundacion Barrié de la Maza y Condesa de Fenosa, and grants FIS PI070392, PI070402, PI10/00038, and PI10/02642 from Instituto de Salud Carlos III. M.U.L. and R.U. were supported by a “Ramón y Cajal” and a “Torres Quevedo” contract from Ministerio de Educación, respectively. M.I.D. and S.B. were supported by the Erasmus program. M.E. was supported by a fellowship from Gobierno de Navarra.

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. Conclusion: 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. (HEPATOLOGY 2011)

Ancillary