Abstract 1597: Claudin-1 expression promote TNF-a-induced epithelial-mesenchymal transition and growth in colorectal adenocarcinoma cells

Abstract

Abstract Epithelial-mesenchymal transition (EMT) is an important mechanism in colorectal cancer progression and malignancy. Importantly, inflammatory mediators are critical constituents of the local tumor environment and an intimate link between colon cancer progression and inflammation in now validated. Notably, we and others have previously reported key role of the deregulated claudin-1, a tight junction protein, in colon carcinogenesis including colitis-associated colon cancer (CAC). Of interest, the increase in claudin-1 expression in CAC was found to be associated with the inflammatory epithelium. We have further demonstrated that inflammation induced by DSS (Dextran Sodium Sulfate) administration promotes colon cancer in APCmin/Claudin-1 transgenic mice. However, what role claudin-1 plays in inflammation-induced colon cancer remains unclear. In current study, we tested the causal significance of claudin-1 expression in inflammation-associated colon cancer using colon cancer cells subjected to TNF-αα, a pro-inflammatory cytokine, treatment. HT29 colon adenocarcinoma cells cultured in the presence of TNF-α (10ng/ml), demonstrated a sharp decrease in E-cadherin expression and an increase in Vimentin expression versus control cells suggesting TNF-αα treatment induced EMT. Also, significant increase in cell proliferation and wound healing was observed in TNF-α treated cells at 24 and 48 hours of TNF-αα treatment (versus control cells). Interestingly, TNF-αα treatment also upregulated (and delocalized) claudin-1 expression in a time-dependent manner. An increase in the phosphorylation of Erk1/2 and Src, signaling associated with colon cancer survival and transformation, in TNF-αα treated cells further correlated with our published observations that claudin-1 expression promotes these signaling pathways in colon cancer cells. In support, shRNA-mediated inhibition of claudin-1 expression in HT-29 cells largely abrogated the effects of TNF-αα treatment including proliferation, p-erk and p-Src expression. Also, TNF-αα induced EMT was largely suppressed in the absence of claudin-1 expression. Taken together, our data confirm the previously described key role of claudin-1 in regulating tumorigenic abilities of colon cancer cells and further highlights a key role of claudin-1 in inflammation-induced colorectal cancer growth and progression. We predict claudin-1 expression can serve as a biomarker to predict CAC progression and malignancy. Citation Format: Ajaz Ahmad Bhat, Rizwan Ahmad, Amar B. Singh, Punita Dhawan. Claudin-1 expression promote TNF-a-induced epithelial-mesenchymal transition and growth in colorectal adenocarcinoma cells. [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 1597.