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Connective tissue growth factor autocriny in human hepatocellular carcinoma: Oncogenic role and regulation by epidermal growth factor receptor/yes‐associated protein–mediated activation
Author(s) -
Urtasun Raquel,
Latasa Maria U.,
Demartis Maria I.,
Balzani Stella,
Goñi Saioa,
GarciaIrigoyen Oihane,
Elizalde Maria,
Azcona Maria,
Pascale Rosa M.,
Feo Francesco,
BioulacSage Paulette,
Balabaud Charles,
Muntané Jordi,
Prieto Jesus,
Berasain Carmen,
Avila Matias A.
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24587
Subject(s) - ctgf , autocrine signalling , cancer research , epidermal growth factor receptor , biology , growth factor , paracrine signalling , carcinogenesis , epidermal growth factor , growth factor receptor , signal transduction , microbiology and biotechnology , receptor , cancer , biochemistry , genetics
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. (H EPATOLOGY 2011)