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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

1,2
,
1,2,3
,
1,2,3
,
1,2,3
,
1,2
and
1,2,3,*
1
Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
2
Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, China
3
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)
View Full-Text   |   Download PDF [4172 KB, uploaded 6 April 2017]   |  

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. 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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