Abstract
BackgroundThe tight junction protein Claudin-1, a claudin family member, has been implicated in several gastro-intestinal pathologies including inflammatory bowel disease (IBD) and colorectal cancer (CRC). In this regard, we have demonstrated that claudin-1 expression in colon cancer cells potentiates their tumorigenic ability while in vivo expression of claudin-1 in the intestinal epithelial cells (IECs) promotes Notch-activation, inhibits goblet cell differentiation and renders susceptibility to mucosal inflammation. Notably, a key role of inflammation in colon cancer progression is being appreciated. Therefore, we examined whether inflammation plays an important role in claudin-1-dependent upregulation of colon carcinogenesis.MethodsAPCmin mice were crossed with Villin-claudin-1 transgenic mice to generate APC-Cldn1 mice. H&E stained colon tissues were assessed for tumor number, size and histological grade. Additionally, microarray and qPCR analyses of colonic tumors were performed to assess molecular changes due to claudin-1 expression. APC-Cldn1 and APCmin controls were assessed for colonic permeability via rectal administration of FITC-dextran, and bacterial translocation via qPCR analysis of 16S rDNA.ResultsClaudin-1 overexpression in APCmin mice significantly increased (~4-fold) colonic tumor growth and size, and decreased survival. Furthermore, transcriptome analysis supported upregulated proliferation, and increased Wnt and Notch-signaling in APC-Cldn1 mice. APC-Cldn1 mice also demonstrated inhibition of mucosal defense genes while expression of pro-inflammatory genes was sharply upregulated, especially the IL-23/IL-17 signaling. We predict that increased Notch/Wnt-signaling underlie the early onset of adenoma formation in APC-Cldn1 mice. An increase in mucosal permeability due to the adenomas and the inherent barrier defect in these mice further facilitate bacterial translocation into the mucosa to induce inflammation, which in turn promote the tumorigenesis.ConclusionTaken together, these results confirm the role of claudin-1 as a promoter of colon tumorigenesis and further identify the role of the dysregulated antigen-tumor interaction and inflammation in claudin-1-dependent upregulation of colon tumorigenesis.
Highlights
The tight junction protein Claudin-1, a claudin family member, has been implicated in several gastro-intestinal pathologies including inflammatory bowel disease (IBD) and colorectal cancer (CRC)
To determine the role of claudin-1 in colon tumorigenesis, we crossed Villin-Claudin-1-Tg mice with APCMin mice (APC) to generate APCMin-VillinClaudin-1 (APC-Cldn1) mice
It is rare that adenomas of APCMin mice, originating from the colon or small bowel progress to invasive adenocarcinoma, yet we were able to detect an incident of invasion in the Adenomatous polyposis coli gene (APC)-Cldn-1 mice (Figure 1E, Table 1)
Summary
The tight junction protein Claudin-1, a claudin family member, has been implicated in several gastro-intestinal pathologies including inflammatory bowel disease (IBD) and colorectal cancer (CRC). In recent years many claudins have been shown to be important players in several types of cancers, in capacities beyond barrier regulation, when their expression levels/ patterns are altered In most of these studies loss of the TJ proteins have contributed to the deregulation of the mechanical aspects of tumor progression such as migration [1], and invasion [2,3]. Cl-1Tg mice demonstrated enhanced severity of Dextran sodium sulfate (DSS)-induced colitis and impaired recovery from colitis-induced epithelial injury, which was attributed to the decreased mucosal protection due to the loss of the primary component of the goblet cells and anti-microbial defense, Mucin-2 These findings supported a previously reported connection between inflammation and claudin-1 expression using specimens from patients with active IBD and colitis-associated cancer [6,7]
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