Abstract 1334: Overexpression of claudin-1 induces Notch and Wnt signaling to regulate colon carcinogenesis
Authors: Punita Dhawan, Jillian Pope, Ashok Sharma, Mary Kay Washington, Amar B. Singh
Journal: Cancer Research (2012)

Abstract Under physiological conditions, colonic homeostasis is a carefully balanced interplay between stem cells, their progeny, differentiation and cell fate determination. Dysregulation of this harmony signifies susceptibility to neoplastic growth. Colonic epithelium undergoes continuous proliferation, differentiation, and apoptosis along the crypt (crypt bottom to top). Notch signaling is a key regulator of the absorptive/secretory lineage determination. Dysregulation of notch signaling disrupts the normal colonic differentiation and depletes the goblet cell population while immature colonocyte population increases. Importantly, emerging literature suggests that Notch- signaling helps regulate colon cancer growth and progression in association with Wnt signaling. We have previously demonstrated that claudin-1 expression is highly increased in colon cancer and is causally associated with the tumorigenic and metastatic abilities of colon cancer cells. We also reported an inverse relationship between claudin-1 expression and differentiation in colon cancer cells. Here, we show a significant decrease in the goblet cell population (as determined by PAS and Alcian Blue) and Muc-2 expression accompanied with an increase in Carbonic Anhydrase I (CAI) expression, a commonly used marker for colonocytes in Villin-claudin-1 transgenic (Cl-1TG) mice that overexpress claudin-1 in the intestinal epithelium. Further analysis to detect Ki-67 expression suggested increase in colonic proliferation in Cl-1TG mice vs. WT mice. Taken together, these data suggest a role for claudin-1 in the regulation of colonic epithelial differentiation. To further determine the role of claudin-1 overexpression in cancer progression, we crossed Cl-1TG mice with APCmin mice, most widely used mouse model of colon cancer. Notably, APCmin mice develop few colonic tumors (mean=0.8) and have a life span of ∼22.5-23 weeks. Importantly, we noted a ∼4fold increase in the colonic tumor burden in (mean=3.8 tumors) and decrease in life span in APCmin/Cl-1 mice vs. APCmin mice. Also, tumors in APCmin/Cl-1 mice were larger, exhibited high grade of dysplasia and increased nuclear β-catenin (activated Wnt signaling) compared to tumors from APCmin mice. Our further studies using SW480claudin-1 cells {SW480 cells stably overexpressing claudin-1} and SW620siRNA cells {SW620 cells with stable inhibition of claudin-1 expression} demonstrated activation of Notch and Wnt signaling in SW480 cells (APCmutant) overexpressing claudin-1 while inhibited on inhibition of claudin-1. Taken together, our data supported a novel role of claudin-1 in the regulation of Notch and Wnt-signaling and thus colon carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1334. doi:1538-7445.AM2012-1334