Abstract 1084: c-Crk proto-oncogene and TGF-β signaling pathway contribute to transcriptional repression of p120-catenin in non-small cell lung cancer cells

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL As a member of adherens junction, p120-catenin (p120ctn) plays a major role in cell adhesion through stabilization of E-cadherin. p120ctn is transcriptionally down-regulated in non-small cell lung cancer (NSCLC), although the molecular mechanisms underlying p120ctn repression are incompletely defined. Here we further investigated transcriptional regulation of p120ctn in NSCLC. We prepared a promoter reporter plasmid construct that contained p120ctn promoter region from position -1082 to +320 relative to transcription start site. Through serial deletion mutation analysis of the p120ctn promoter, we pinpointed cis-acting elements involved in regulation of p120ctn. We identified transcription factor SP1 as a transcriptional repressor of p120ctn that directly binds to segment (−9 to +36) of the p120ctn promoter. SP1 can receive multiple signals from several intracellular signaling pathways. Through examination of SP1 binding partners, we identified proto-oncogene c-Crk and TGF-β signaling pathway to be involved in transcriptional down-regulation of p120ctn. RNAi mediated silencing of CRK in A549, H157 and H358 cells increased p120ctn protein levels. On the other hand, over-expression of CRK-I in H358 cells down-regulated p120ctn, an effect that was abrogated by simultaneous silencing of SP1. We also observed that CRK-II serine phosphorylation was inversely correlated with p120ctn expression level. This finding suggests a role for serine/threonine kinases in promoting metastasis through phosphorylation of CRK I/II and subsequently down-regulation of p120ctn. In summary, our data provide evidence for the role of c-Crk proto-oncogene and TGF-β signaling in transcriptional repression of p120ctn that further clarifies the mechanism by which these biochemical signals promote metastasis in NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1084. doi:10.1158/1538-7445.AM2011-1084