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

• Published in: International journal of molecular sciences Vol. 18; no. 4; p. 765
• Main Authors: Wang, Yaxi, Sun, Tingyi, Sun, Haimei, Yang, Shu, Li, Dandan, Zhou, Deshan
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06-04-2017; MDPI
• Subjects: Activator protein 1; Animal models; Animals; Biotechnology; c-Jun N-terminal kinase; c-Jun protein; c-kit; c-Kit protein; Cell adhesion; Cell adhesion & migration; Cell Line, Tumor; Chromatin; claudin-3; Claudin-3 - metabolism; claudins; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - metabolism; Epithelium; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Immunoprecipitation; In vitro methods and tests; Intestinal Mucosa - metabolism; Intestine; Kinases; MAP Kinase Signaling System; Mice; Neoplasm Transplantation; Polarity; Proteins; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Rodents; Signal transduction; Solid tumors; Stem cell factor; Stem Cell Factor - metabolism; Stem cells; Tight junctions; Transcription Factor AP-1 - metabolism; Transcription factors; Tumors; c-Jun N-terminal kinase; claudin-3; colorectal cancer; claudins; c-kit; activator protein-1
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms18040765

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
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
promoter and enhanced its transcription activity. Furthermore, decreased expression of claudin-3 was obtained in the colonic epithelium from the
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.