Abstract
Claudin-3 is a major protein of tight junctions (TJs) in the intestinal epithelium and is critical for maintaining cell-cell adhesion, barrier function, and epithelium polarity. Recent studies have shown high claudin-3 levels in several solid tumors, but the regulation mechanism of claudin-3 expression remains poorly understood. In the present study, colorectal cancer (CRC) tissues, HT-29 and DLD-1 CRC cell lines, CRC murine model (C57BL/6 mice) and c-kit loss-of-function mutant mice were used. We demonstrated that elevated claudin-3 levels were positively correlated with highly expressed c-kit in CRC tissues based upon analysis of protein expression. In vitro, claudin-3 expression was clearly increased in CRC cells by overexpressed c-kit or stimulated by exogenous recombinant human stem cell factor (rhSCF), while significantly decreased by the treatment with c-kit or c-Jun N-terminal kinase (JNK) inhibitors. Chromatin immunoprecipitation (ChIP) and luciferase reporter assay showed that SCF/c-kit signaling significantly promoted activator protein-1 (AP-1) binding with CLDN-3 promoter and enhanced its transcription activity. Furthermore, decreased expression of claudin-3 was obtained in the colonic epithelium from the c-Kit loss-of-function mutant mice. In conclusion, SCF/c-kit-JNK/AP-1 signaling pathway significantly promoted claudin-3 expression in colonic epithelium and CRC, which could contribute to epithelial barrier function maintenance and to CRC development.
Highlights
Claudins are the major components of tight junctions (TJs) in the epithelium, and 27 family members widely distribute in different tissues
Previous studies suggested that activation of c-kit signaling [20] and overexpression of claudin-3 [21] were both involved in colorectal cancer (CRC) development
We found that the increased phosphorylation of Jun N-terminal kinase (JNK) and c-Jun was often accompanied by highly expressed claudin-3 in colonic epithelium and CRC cells
Summary
Claudins are the major components of tight junctions (TJs) in the epithelium, and 27 family members widely distribute in different tissues. It is well known that claudins play important roles in maintaining cell-cell adhesion, barrier function, and epithelial physiological polarity [1,2]. Claudin-3 is mainly expressed in basolateral membrane and the apical of the epithelium and is a main protein of TJs in the intestinal epithelium. Its absence often results in leaky paracellular permeability, which plays an important role in the pathogenesis of inflammatory bowel diseases [4]. It has been reported that claudin-3 was highly expressed in ovarian cancers, but hardly detected in normal ovarian epithelium [5], thereby, claudin-3 was considered to be a promising target for diagnosis and treatment in ovarian cancers [6]
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