Hepatocyte growth factor regulates cyclooxygenase-2 expression via {beta}-catenin, Akt, and p42/p44 MAPK in human bronchial epithelial cells

1 Department of Pharmacology, The Uniformed Services University of the Health Sciences, Bethesda, Maryland; and 2 Department of Pharmacology, Georgetown University Medical Center, Washington, DC Submitted 4 October 2007 ; accepted in final form 26 January 2008 Hepatocyte growth factor (HGF) is upregulated in response to lung injury and has been implicated in tissue repair through its antiapoptotic and proliferative activities. Cyclooxygenase-2 (COX-2) is an inducible enzyme in the biosynthetic pathway of prostaglandins, and its activation has been shown to play a role in cell growth. Here, we report that HGF induces gene transcription of COX-2 in human bronchial epithelial cells (HBEpC). Treatment of HBEpC with HGF resulted in phosphorylation of the HGF receptor (c-Met), activation of Akt, and upregulation of COX-2 mRNA. Adenovirus-mediated gene transfer of a dominant negative (DN) Akt mutant revealed that HGF increased COX-2 mRNA in an Akt-dependent manner. COX-2 promoter analysis in luciferase reporter constructs showed that HGF regulation required the β-catenin-responsive T cell factor-4 binding element (TBE). The HGF activation of the COX-2 gene transcription was blocked by DN mutant of β-catenin or by inhibitors that blocked activation of Akt. Inhibition of p42/p44 MAPK pathway blocked HGF-mediated activation of β-catenin gene transcription but not Akt activation, suggesting that p42/p44 MAPK acts in a parallel mechanism for β-catenin activation. We also found that inhibition of COX-2 with NS-398 blocked HGF-induced growth in HBEpC. Together, the results show that the HGF increases COX-2 gene expression via an Akt-, MAPK-, and β-catenin-dependent pathway in HBEpC. fibrosis; signal transduction; proliferation; tissue repair; T cell factor-4 binding element Address for reprint requests and other correspondence: R. M. Day, Dept. of Pharmacology, Bldg. C, Rm. 2023, 4301 Jones Bridge Rd., Bethesda, MD 20814-4799 (e-mail: rday{at}usuhs.mil )