Abstract 1059: Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion

Abstract

Abstract Esophageal cancer is one of the most common malignancies and leading causes of cancer deaths worldwide. Esophageal squamous cell carcinoma accounts for the majority of esophageal cancers but in recent years the incidence of esophageal adenocarcinoma has increased dramatically, particularly in Western countries. Esophageal cancers are highly invasive and metastatic, which account for the high rate of cancer death. However, the exact molecular mechanisms that contribute to the initiation and progression of esophageal cancer remain unclear. LKB1 is a tumor susceptibility gene for the Peutz-Jeghers cancer syndrome (PJS) and is a target for mutational inactivation in sporadic human malignancies. LKB1 encodes a serine/threonine kinase that plays critical roles in cell growth, polarity and metabolism. A novel and important function of LKB1 is its ability to regulate the phosphorylation of CREB-regulated transcriptional co-activators (CRTC) whose aberrant activation is linked with oncogenic activities. However, the roles and mechanisms of LKB1 and CRTC in the pathogenesis of esophageal cancer have not been previously investigated. In this study, we observed altered LKB1-CRTC signaling in a subset of human esophageal cancer cell lines and patient samples. LKB1 negatively regulates esophageal cancer cell migration and invasion in vitro. Mechanistically, we determined that CRTC signaling becomes activated due to LKB1 loss, which results in the transcriptional activation of specific downstream targets including LYPD3, a critical mediator for LKB1-loss of function. Our study indicates that de-regulated LKB1-CRTC signaling might represent a crucial mechanism for esophageal cancer progression. Our data warrant future studies to understand the importance of LKB1 and CRTC signaling in esophageal cancers and to investigate CRTC activation as a target for cancers with LKB1 down-regulation. 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 1059. doi:10.1158/1538-7445.AM2011-1059