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

Oncogene volume 36, pages 6592–6604 (2017)Cite this article

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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.

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Acknowledgements

This work was supported by BX002086 (PD), DK088902 and BX002761 (ABS).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

    R Ahmad, B Kumar, S K Batra, P Dhawan & A B Singh

  2. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China,

    Z Chen

  3. Division of Biostatistics, University of Miami Miller School of Medicine, Miami, FL, USA

    X Chen

  4. Department of Pediatric Nephrology, Charité, and Berlin Institute of Health, Berlin, Germany

    D Müller

  5. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    S M Lele

  6. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    M K Washington

  7. VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA

    P Dhawan & A B Singh

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Ahmad, R., Kumar, B., Chen, Z. et al. Loss of claudin-3 expression induces IL6/gp130/Stat3 signaling to promote colon cancer malignancy by hyperactivating Wnt/β-catenin signaling. Oncogene 36, 6592–6604 (2017). https://doi.org/10.1038/onc.2017.259

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