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2015 ; 34
(35
): 4570-80
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Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to
inhibit colon tumorigenesis
#MMPMID25500541
Bhat AA
; Pope JL
; Smith JJ
; Ahmad R
; Chen X
; Washington MK
; Beauchamp RD
; Singh AB
; Dhawan P
Oncogene
2015[Aug]; 34
(35
): 4570-80
PMID25500541
show ga
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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