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N‐cadherin Upregulation and EMT Progression in As 3+ and Cd 2+ ‐Transformed Urothelial Cells
Author(s) -
Sandquist Elizabeth,
Somji Seema,
Sens Donald,
Garrett Scott
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.629.8
Subject(s) - downregulation and upregulation , cadherin , bladder cancer , epithelial–mesenchymal transition , cancer research , malignant transformation , cancer , microarray analysis techniques , chemistry , biology , cell , medicine , gene expression , gene , genetics
Environmental agents are common causes of bladder cancer. Specifically, As 3+ and Cd 2+ are carcinogens implicated in bladder cancer development. Studies from our laboratory show that As 3+ and Cd 2+ cause malignant transformation of immortalized bladder urothelial cells, which form tumors in nude mice. Microarray analysis of repeated metal transformation in parallel revealed that N‐cadherin was the most upregulated gene in As 3+ transformants, and a top induced gene in Cd 2+ transformed cells. The E‐ to N‐cadherin switch is a well‐known indicator of the epithelial‐to‐mesenchymal transition (EMT) in cancer. N‐cadherin is correlated with tumor stage, increased recurrence, and decreased survival. While factors mediating E‐cadherin are well established, little is known of the regulation of N‐cadherin. The goal of the present study was to determine if N‐cadherin upregulation is maintained in animal models, the mechanism by which metal transformation leads to sustained N‐cadherin expression, and if this elevation is involved in EMT. Both mRNA and protein levels of N‐cadherin were increased in As 3+ and Cd 2+ transformed cell isolates, with focal expression present in intraperitoneal tumor heterotransplants. Twist and Snail were also elevated, indicating EMT. N‐cadherin may be epigenetically regulated, as MS‐275 and 5‐azacytidine altered N‐cadherin levels. Exposure of nontransformed urothelial cells to As 3+ induced N‐cadherin, suggesting that heavy metal exposure promotes bladder cancer progression and EMT. Grant Funding Source: ND INBRE: 8P20GM103442‐14 from NIGMS and R25 ES016250 from NIEHS