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Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis

Oncogene volume 34, pages 4570–4580 (2015)Cite this article

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Abstract

In normal colon, claudin-7 is one of the highly expressed claudin proteins and its knockdown in mice results in altered epithelial cell homeostasis and neonatal death. Notably, dysregulation of the epithelial homeostasis potentiates oncogenic transformation and growth. However, the role of claudin-7 in the regulation of colon tumorigenesis remains poorly understood. Using a large colorectal cancer (CRC) patient database and mouse models of colon cancer, we found claudin-7 expression to be significantly downregulated in cancer samples. Most notably, forced claudin-7 expression in poorly differentiated and highly metastatic SW620 colon cancer cells induced epithelial characteristics and inhibited their growth in soft agar and tumor growth in vivo. By contrast, knockdown of claudin-7 in HT-29 or DLD-1 cells induced epithelial-to-mesenchymal transition (EMT), colony formation, xenograft-tumor growth in athymic mice and invasion. Importantly, a claudin-7 signature gene profile generated by overlapping the DEGs (differentially expressed genes in a high-throughput transcriptome analysis using claudin-7-manipulated cells) with human claudin-7 signature genes identified high-risk CRC patients. Furthermore, Rab25, a colon cancer suppressor and regulator of the polarized cell trafficking constituted one of the highly upregulated DEGs in claudin-7 overexpressing cells. Notably, silencing of Rab25 expression counteracted the effects of claudin-7 expression and not only increased proliferation and cell invasion but also increased the expression of p-Src and mitogen-activated protein kinase–extracellular signal–regulated kinase 1/2 that were suppressed upon claudin-7 overexpression. Of interest, CRC cell lines, which exhibited decreased claudin-7 expression, also exhibited promoter DNA hypermethylation, a modification associated with transcriptional silencing. Taken together, our data demonstrate a previously undescribed role of claudin-7 as a colon cancer suppressor and suggest that loss of claudin-7 potentiates EMT to promote colon cancer, in a manner dependent on Rab25.

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Acknowledgements

We are thankful to John Neff and Jalal Hamaamen for their technical support. This work was supported by VA-merit BX002086 and CA124977 (to PD), DK088902 (to ABS), CA158472 (to XC and RDB), CA069457 (to RDB), GI Cancer SPORE grant CA095103, Vanderbilt DDRC P30DK058404, VICC P30CA68485 and StarBRITE funds (no. VR1258).

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Authors and Affiliations

  1. Department of Veterans Affairs, Tennessee Valley Healthcare System, Vanderbilt University Medical Center, Nashville, TN, USA

    A A Bhat, J L Pope, R Ahmad & P Dhawan

  2. Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA

    J L Pope

  3. Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

    J J Smith, R D Beauchamp, A B Singh & P Dhawan

  4. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    X Chen & A B Singh

  5. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA

    M K Washington

  6. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    R D Beauchamp & P Dhawan

  7. Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    R D Beauchamp

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Correspondence to P Dhawan.

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Bhat, A., Pope, J., Smith, J. et al. Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis. Oncogene 34, 4570–4580 (2015). https://doi.org/10.1038/onc.2014.385

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