Loss of claudin-3 expression induces IL6/gp130/Stat3 signaling to promote colon cancer malignancy by hyperactivating Wnt/β-catenin signaling

• Published in: Oncogene Vol. 36; no. 47; pp. 6592 - 6604
• Main Authors: Ahmad, R, Kumar, B, Chen, Z, Chen, X, Müller, D, Lele, S M, Washington, M K, Batra, S K, Dhawan, P, Singh, A B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-11-2017; Nature Publishing Group
• Subjects: 13; 14/19; 14/63; 38/109; 38/77; 631/67/1504/1885; 631/80/86/2368; 64/60; 82/29; 82/51; 82/80; Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - mortality; Adenocarcinoma - pathology; Adenoma; Animals; Apoptosis; beta Catenin - metabolism; Carcinogenesis - metabolism; Cell Biology; Cell Transformation, Neoplastic; Claudin-3 - genetics; Claudin-3 - metabolism; Colon - metabolism; Colon cancer; Colonic Neoplasms - metabolism; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Cytokine Receptor gp130 - metabolism; Epigenesis, Genetic; Epigenetics; Epithelial-Mesenchymal Transition; Epithelium; Gene Expression Regulation, Neoplastic; Glycoprotein gp130; Homeostasis; Human Genetics; Humans; Interleukin 6; Internal Medicine; Intestinal Mucosa - metabolism; Invasiveness; Malignancy; Medicine; Medicine & Public Health; Mesenchyme; Mice; Mice, Knockout; Mucosa; Oncology; original-article; Permeability; Signal transduction; Stat3 protein; STAT3 Transcription Factor - metabolism; Therapeutic targets; Tumorigenesis; Up-Regulation; Wnt protein; Wnt Signaling Pathway; β-Catenin
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.259

The hyperactivated Wnt/β-catenin signaling acts as a switch to induce epithelial to mesenchymal transition and promote colorectal cancer. However, due to its essential role in gut homeostasis, therapeutic targeting of this pathway has proven challenging. Additionally, IL-6/Stat-3 signaling, activated by microbial translocation through the dysregulated mucosal barrier in colon adenomas, facilitates the adenoma to adenocarcinomas transition. However, inter-dependence between these signaling pathways and key mucosal barrier components in regulating colon tumorigenesis and cancer progression remains unclear. In current study, we have discovered, using a comprehensive investigative regimen, a novel and tissue-specific role of claudin-3, a tight junction integral protein, in inhibiting colon cancer progression by serving as the common rheostat of Stat-3 and Wnt-signaling activation. Loss of claudin-3 also predicted poor patient survival. These findings however contrasted an upregulated claudin-3 expression in other cancer types and implicated role of the epigenetic regulation. Claudin-3−/− mice revealed dedifferentiated and leaky colonic epithelium, and developed invasive adenocarcinoma when subjected to colon cancer. Wnt-signaling hyperactivation, albeit in GSK-3β independent manner, differentiated colon cancer in claudin-3−/− mice versus WT-mice. Claudin-3 loss also upregulated the gp130/IL6/Stat3 signaling in colonic epithelium potentially assisted by infiltrating immune components. Genetic and pharmacological studies confirmed that claudin-3 loss induces Wnt/β-catenin activation, which is further exacerbated by Stat-3-activation and help promote colon cancer. Overall, these novel findings identify claudin-3 as a therapeutic target for inhibiting overactivation of Wnt-signaling to prevent CRC malignancy.