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

Abstract

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.

• Authors: R Ahmad, B Kumar, Z Chen, X Chen, D Müller, S M Lele, M K Washington, S K Batra, P Dhawan, A B Singh
• Journal: Oncogene (Oncogene) Vol. 36 Issue 47 Pg. 6592-6604 (11 23 2017) ISSN: 1476-5594 [Electronic] England
• PMID: 28783170 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• CLDN3 protein, human
• CTNNB1 protein, human
• Claudin-3
• IL6ST protein, human
• STAT3 Transcription Factor
• STAT3 protein, human
• beta Catenin
• Cytokine Receptor gp130

Topics

• Adenocarcinoma (genetics, mortality, pathology)
• Animals
• Carcinogenesis (metabolism)
• Cell Transformation, Neoplastic
• Claudin-3 (genetics, metabolism)
• Colon (metabolism)
• Colonic Neoplasms (metabolism)
• Colorectal Neoplasms (genetics, mortality, pathology)
• Cytokine Receptor gp130 (metabolism)
• Epigenesis, Genetic
• Epithelial-Mesenchymal Transition
• Gene Expression Regulation, Neoplastic
• Humans
• Intestinal Mucosa (metabolism)
• Mice
• Mice, Knockout
• Permeability
• STAT3 Transcription Factor (metabolism)
• Up-Regulation
• Wnt Signaling Pathway
• beta Catenin (metabolism)