title: SCF/C-Kit/JNK/AP-1 Signaling Pathway Promotes Claudin-3 Expression in Colonic Epithelium and Colorectal Carcinoma.
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) andc-kitloss-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 withCLDN-3promoter and enhanced its transcription activity. Furthermore, decreased expression of claudin-3 was obtained in the colonic epithelium from thec-Kitloss-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.
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. wangyaxi1@sina.com.|Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, China. wangyaxi1@sina.com.
authors.forename: Yaxi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. styj211@ccmu.edu.cn.|Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, China. styj211@ccmu.edu.cn.|Cancer Institute of Capital Medical University, Beijing 100069, China. styj211@ccmu.edu.cn.
authors.forename: Tingyi
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. haimei@ccmu.edu.cn.|Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, China. haimei@ccmu.edu.cn.|Cancer Institute of Capital Medical University, Beijing 100069, China. haimei@ccmu.edu.cn.
authors.forename: Haimei
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. sheilayslamb@aliyun.com.|Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, China. sheilayslamb@aliyun.com.|Cancer Institute of Capital Medical University, Beijing 100069, China. sheilayslamb@aliyun.com.
authors.forename: Shu
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. lidan0135@sina.com.|Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, China. lidan0135@sina.com.
authors.forename: Dandan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. zhouds08@ccmu.edu.cn.|Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, China. zhouds08@ccmu.edu.cn.|Cancer Institute of Capital Medical University, Beijing 100069, China. zhouds08@ccmu.edu.cn.
authors.forename: Deshan
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D062465:Claudin-3 / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D009368:Neoplasm Transplantation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D019089:Stem Cell Factor / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D062465:Claudin-3; D019089:Stem Cell Factor; D018808:Transcription Factor AP-1; D019009:Proto-Oncogene Proteins c-kit
keywords: activator protein-1; c-Jun N-terminal kinase; c-kit; claudin-3; claudins; colorectal cancer