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Int. J. Mol. Sci. 2017, 18(4), 765; doi:10.3390/ijms18040765

SCF/C-Kit/JNK/AP-1 Signaling Pathway Promotes Claudin-3 Expression in Colonic Epithelium and Colorectal Carcinoma

Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, China
Cancer Institute of Capital Medical University, Beijing 100069, China
Author to whom correspondence should be addressed.
Academic Editor: Atsushi Matsuzawa
Received: 4 March 2017 / Revised: 29 March 2017 / Accepted: 30 March 2017 / Published: 6 April 2017
(This article belongs to the Special Issue Kinase Signal Transduction 2017)
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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. View Full-Text
Keywords: claudins; colorectal cancer; c-kit; claudin-3; c-Jun N-terminal kinase; activator protein-1 claudins; colorectal cancer; c-kit; claudin-3; c-Jun N-terminal kinase; activator protein-1

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Wang, Y.; Sun, T.; Sun, H.; Yang, S.; Li, D.; Zhou, D. SCF/C-Kit/JNK/AP-1 Signaling Pathway Promotes Claudin-3 Expression in Colonic Epithelium and Colorectal Carcinoma. Int. J. Mol. Sci. 2017, 18, 765.

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