Abstract 1342: Loss of claudin-3 expression induces IL6/gp130/Stat3 signaling to promote colon cancer malignancy
Authors: Ahmad Rizwan , kumar Balawant , Chen Zhimin , Chen Steven(Xi) , Muller Dominik , Lele Subodh M. , Washington Mary Kay , Batra Surinder K. , Dhawan Punita , Singh Amar B. 
Published: July 2017

Abstract
Genetic and epigenetic aberrations drive the formation of a benign colorectal adenoma and its progression to the full-blown carcinoma. Hyperactivated Wnt/β-catenin signaling acts as a switch to induce EMT and promote colorectal cancer. Additionally, IL-6/Stat-3 signaling, activated by microbial translocation through the dysregulated mucosal barrier in colon adenomas, facilitates the adenoma to adenocarcinomas transition. However, inter-dependence between these signaling pathways in their capacity to communicate with mucosal barrier to promote colon cancer remains unclear. In current study, we have discovered, using a comprehensive investigative regimen, a novel and tissue specific role of claudin-3, tight junction integral protein, in inhibiting colon cancer progression by serving as the common rheostat of Stat-3 and Wnt-signaling activation. Notably, in our analysis, using mRNA and protein expression, and utilizing samples from a large patient cohort (&lt;250 CRC specimen), we found claudin-3 expression to be significantly suppressed (p&lt;0.001 versus normal) in cancer tissues versus normal mucosa. The colon tissues from the established mouse models of colon cancer (APCmin mice and Azoxymethane (AOM)-DSS-induced colon cancer) demonstrated similar tumor specific decrease in claudin-3 expression. Interestingly, claudin-3 negative tumors retained E-cadherin expression. Most notably, we found a significant and positive correlation (p&lt;0.05) of the greater levels of claudin-3 expression with patient survival. These findings however contrasted an upregulated claudin-3 expression in other cancer types and implicated differential epigenetic regulation. In further studies, naïve claudin-3-/- mice revealed dedifferentiated {significant down regulation of P-27 (p&lt;0.05) and vimentin expression versus WT mice} and leaky colonic epithelium. Moreover, claudin-3-/- mice demonstrated increased colon tumor burden and invasive adenocarcinoma when subjected to colon cancer. Wnt-signaling hyperactivation, albeit in GSK-3β independent manner, characterized colon cancer in claudin-3-/- mice. Claudin-3 loss also upregulated the gp130/IL6/Stat3 signaling in colonic epithelium potentially assisted by infiltrating immune organization. Genetic and pharmacological studies confirmed that claudin-3 loss induces Wnt/β-catenin activation in Stat-3-dependent manner to promote colon cancer. Overall, these novel findings identify claudin-3 as a therapeutic target for inhibiting overactivation of Wnt-signaling to prevent CRC malignancy.
Citation Format: Rizwan Ahmad, Balawant kumar, Zhimin Chen, Steven(Xi) Chen, Dominik Muller, Subodh M. Lele, Mary Kay Washington, Surinder K. Batra, Punita Dhawan, Amar B. Singh. Loss of claudin-3 expression induces IL6/gp130/Stat3 signaling to promote colon cancer malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1342. doi:10.1158/1538-7445.AM2017-1342