Abstract 4114: Blocking Ezrin can inhibit HGF/Met signaling-induced metastasis

Abstract

Abstract Hepatocyte Growth Factor (HGF) binds its receptor Met and induces autophosphorylation of MET, which in turn activate appropriate signaling pathways. Aberrant HGF/Met signaling promotes tumor progression by facilitating cell proliferation, migration, invasion, and metastasis. Previously, we found that constitutive HGF/Met signaling promotes melanoma metastasis through a nonautocrine mechanism in engineered mouse models (Cancer Res, 2002); however, the molecular mechanisms by downstream of HGF/Met signaling that induce metastasis are not known. We recently identified the cytoskeletal organizer Ezrin as a key metastatic regulator using an HGF transgenic mouse model (Nature Medicine, 2004), implicating Ezrin is in HGF/Met signaling-induced metastasis. We hypothesize that HGF/Met signaling promotes metastasis by regulating expression of Ezrin. To test hypothesis, we are: 1) evaluating the relationship between ezrin expression and HGF/Met signaling; 2) validating the role of Ezrin in HGF/Met signaling -induced metastasis; 3) elaborating mechanisms underlying this HGF/Met signaling-mediated regulation of Ezrin expression; 4) evaluating the clinical therapeutic utility of blockage of Ezrin function in preclinical mouse models. We found that HGF is able to stimulate the expression of Ezrin. Moreover, analysis of the established model systems with HGF and Met alone or HGF with Met demonstrated that Ezrin expression correlated with activated HGF/Met signaling, suggesting that HGF/Met signaling regulates the expression of Ezrin. Interestingly, we showed that HGF/Met signaling could activate transcription factor Sp1 through the MAPK pathway. We further found that activated Sp1 could directly bind to the promoter of the Ezrin gene and regulate the transcription of Ezrin. Notably, knockdown of Ezrin expression by shRNAs inhibited the metastasis induced by both HGF/Met autocrine and notautocrine signaling in syngeneic host and HGF GEM hosts. We also used small molecule drugs in preclinical mouse models to confirm that Ezrin is at least one of downstream molecules mediating HGF/Met signaling-induced metastasis in melanoma. We conclude that Ezrin is a key downstream substrate involved in the regulation of HGF/Met signaling-induced metastasis. We demonstrate a link between Ezrin and HGF/Met/MAPK/Sp1 activation in the metastatic process. Our data indicate that Ezrin represents a promising therapeutic target for patients with activated HGF/Met signaling. Citation Format: Yanlin Yu, Liping Huang, Glenn Merlino. Blocking Ezrin can inhibit HGF/Met signaling-induced metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4114.