title: Epithelial-mesenchymal transition promotes SOX2 and NANOG expression in bladder cancer.
abstract: Bladder cancer is the most common malignant tumor of the urothelium and is classified into non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Stemness markers such as SOX2 and NANOG are frequently overexpressed in various aggressive cancers, including MIBC; epithelial-mesenchymal transition (EMT) has been proposed as a potential trigger of stemness in cancers. To determine whether cancer stemness is acquired via EMT in bladder cancer, we studied the effect of EMT on the expression of SOX2 and NANOG in bladder cancer cell lines. We also analyzed their expression in clinical tissue samples. Our results revealed that a potent EMT inducer (transforming growth factor β1) reduced the expression of the epithelial marker E-cadherin and increased expression of both SOX2 and NANOG in epithelial-type bladder cancer cells. As for clinical bladder cancer samples, in NMIBC, E-cadherin expression was slightly diminished, and the expression of both SOX2 and NANOG was negligible. In contrast, in MIBC, E-cadherin expression was highly and heterogeneously diminished, while the expression of both SOX2 and NANOG was increased. We also noticed that either E-cadherin or SOX2 (or NANOG) was expressed (ie, in a manner exclusive of each other). In addition, the concentration of E-cadherin showed a significant negative correlation with tumor grade and stage, while expression of SOX2 and NANOG positively correlated with those clinicopathological parameters. These findings suggest that EMT promotes stemness of bladder cancer cells, contributing to tumor aggressiveness. This EMT-cancer stemness axis may also play an important role in the pathogenesis of NMIBC and MIBC.Laboratory Investigation advance online publication, 27 February 2017; doi:10.1038/labinvest.2017.17.
authors.affiliation: Department of Molecular Medical Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.|Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Migita
authors.affiliation: Department of Molecular Medical Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.|Services & Digital Consulting Department, Hitachi Consulting Co., Ltd., Tokyo, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Ueda
authors.affiliation: Department of Molecular Medical Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.|Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.|Institute of Microbial Chemistry, Numazu, Shizuoka, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Ohishi
authors.affiliation: Department of Molecular Medical Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.|Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.|Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Hatano
authors.affiliation: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Seimiya
authors.affiliation: Department of Pathology, Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan.
authors.forename: Shin-Ichiro
authors.initials: SI
authors.lastname: Horiguchi
authors.affiliation: Department of Urology, Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Koga
authors.affiliation: Department of Molecular Medical Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Shibasaki