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

Ajaz Ahmad Bhat, J. L. Pope, J. J. Smith, R. Ahmad, X. Chen, M. K. Washington, R. D. Beauchamp, A. B. Singh, P. Dhawan

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4570-4580
Number of pages11
JournalOncogene
Volume34
Issue number35
DOIs
Publication statusPublished - 27 Aug 2015
Externally publishedYes

Fingerprint

Epithelial-Mesenchymal Transition
Colonic Neoplasms
Colon
Carcinogenesis
Colorectal Neoplasms
Growth
Homeostasis
Epithelial Cells
Claudins
Genes
Neoplasms
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Gene Expression Profiling
Mitogen-Activated Protein Kinases
Heterografts
Nude Mice
Agar
Cell Death
Down-Regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Bhat, A. A., Pope, J. L., Smith, J. J., Ahmad, R., Chen, X., Washington, M. K., ... Dhawan, P. (2015). Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis. Oncogene, 34(35), 4570-4580. https://doi.org/10.1038/onc.2014.385

Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis. / Bhat, Ajaz Ahmad; Pope, J. L.; Smith, J. J.; Ahmad, R.; Chen, X.; Washington, M. K.; Beauchamp, R. D.; Singh, A. B.; Dhawan, P.

In: Oncogene, Vol. 34, No. 35, 27.08.2015, p. 4570-4580.

Research output: Contribution to journalArticle

Bhat, AA, Pope, JL, Smith, JJ, Ahmad, R, Chen, X, Washington, MK, Beauchamp, RD, Singh, AB & Dhawan, P 2015, 'Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis', Oncogene, vol. 34, no. 35, pp. 4570-4580. https://doi.org/10.1038/onc.2014.385
Bhat, Ajaz Ahmad ; Pope, J. L. ; Smith, J. J. ; Ahmad, R. ; Chen, X. ; Washington, M. K. ; Beauchamp, R. D. ; Singh, A. B. ; Dhawan, P. / Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis. In: Oncogene. 2015 ; Vol. 34, No. 35. pp. 4570-4580.
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