1. Regulation of amphiregulin gene expression by β-catenin signaling in human hepatocellular carcinoma cells: a novel crosstalk between FGF19 and the EGFR system
- Author
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Carmen Berasain, Matías A. Avila, Maria U. Latasa, Monica Santamaria, Jesús Prieto, M.R. Elizalde, Francesco Feo, Iker Uriarte, Rosa Maria Pascale, Fabiana Salis, Oihane Garcia-Irigoyen, and Raquel Urtasun
- Subjects
Gene Expression ,lcsh:Medicine ,Fibroblast growth factor ,medicine.disease_cause ,Biochemistry ,Transcription Factor 4 ,Molecular Cell Biology ,Signaling in Cellular Processes ,Cyclin D1 ,Epidermal growth factor receptor ,Biomacromolecule-Ligand Interactions ,Promoter Regions, Genetic ,lcsh:Science ,Crosstalk ,beta Catenin ,Regulation of gene expression ,Multidisciplinary ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,Liver Diseases ,Mechanisms of Signal Transduction ,Liver Neoplasms ,Beta-Catenin Signaling ,Prognosis ,ErbB Receptors ,Gene Expression Regulation, Neoplastic ,Oncology ,MED/04 Patologia generale ,Medicine ,Intercellular Signaling Peptides and Proteins ,Signal transduction ,Research Article ,Signal Transduction ,EGF Family of Proteins ,Carcinoma, Hepatocellular ,Beta-catenin ,Gastroenterology and Hepatology ,Biology ,Amphiregulin ,Cell Line, Tumor ,Gastrointestinal Tumors ,Genetics ,medicine ,Humans ,Cell Proliferation ,Glycoproteins ,lcsh:R ,Cancers and Neoplasms ,Hepatocellular Carcinoma ,digestive system diseases ,Fibroblast Growth Factors ,Mutation ,biology.protein ,Cancer research ,lcsh:Q ,Carcinogenesis ,Transcription Factors - Abstract
Hepatocellular carcinoma (HCC) is the most prevalent liver tumor and a deadly disease with limited therapeutic options. Dysregulation of cell signaling pathways is a common denominator in tumorigenesis, including hepatocarcinogenesis. The epidermal growth factor receptor (EGFR) signaling system is commonly activated in HCC, and is currently being evaluated as a therapeutic target in combination therapies. We and others have identified a central role for the EGFR ligand amphiregulin (AR) in the proliferation, survival and drug resistance of HCC cells. AR expression is frequently up-regulated in HCC tissues and cells through mechanisms not completely known. Here we identify the ß-catenin signaling pathway as a novel mechanism leading to transcriptional activation of the AR gene in human HCC cells. Activation of ß-catenin signaling, or expression of the T41A ß-catenin active mutant, led to the induction of AR expression involving three specific ß-catenin-Tcf responsive elements in its proximal promoter. We demonstrate that HCC cells expressing the T41A ß-catenin active mutant show enhanced proliferation that is dependent in part on AR expression and EGFR signaling. We also demonstrate here a novel cross-talk of the EGFR system with fibroblast growth factor 19 (FGF19). FGF19 is a recently identified driver gene in hepatocarcinogenesis and an activator of ß-catenin signaling in HCC and colon cancer cells. We show that FGF19 induced AR gene expression through the ß-catenin pathway in human HCC cells. Importantly, AR up-regulation and EGFR signaling participated in the induction of cyclin D1 and cell proliferation elicited by FGF19. Finally, we demonstrate a positive correlation between FGF19 and AR expression in human HCC tissues, therefore supporting in clinical samples our experimental observations. These findings identify the AR/EGFR system as a key mediator of FGF19 responses in HCC cells involving ß-catenin signaling, and suggest that combined targeting of FGF19 and AR/EGFR may enhance therapeutic efficacy.
- Published
- 2012