GPX2 promotes development of bladder cancer with squamous cell differentiation through the control of apoptosis
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Taku Naiki1,2, Aya Naiki-Ito1, Keitaro Iida2, Toshiki Etani2, Hiroyuki Kato1, Shugo Suzuki1, Yoriko Yamashita1, Noriyasu Kawai2, Takahiro Yasui2 and Satoru Takahashi1
1Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
2Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
Aya Naiki-Ito, email: [email protected]
Keywords: GPX2; oxidative stress; bladder cancer; squamous differentiation
Received: October 27, 2017 Accepted: February 27, 2018 Published: March 23, 2018
Herein, we elucidated the molecular mechanisms and therapeutic potential of glutathione peroxidase 2 (GPX2) in bladder cancer. GPX2 expression gradually increased during progression from normal to papillary or nodular hyperplasia (PNHP) and urothelial carcinoma (UC) in a rat N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder carcinogenesis model. GPX2 overexpression was more marked in UC with squamous differentiation (SqD) than in pure UC. Clinical intraepithelial lesions of papillary UC and invasive UC with SqD also had strong GPX2 expression in human radical cystectomy specimens. In addition, prognostic analysis using transurethral specimens revealed that low expression level of GPX2 predicted poor prognosis in patients with pure UC. Further, UC cell lines, BC31 and RT4, cultured in vitro also overexpressed GPX2. Knock-down of GPX2 induced significant inhibition of intracellular reactive oxygen species (ROS) production, in addition to significant growth inhibition and increased apoptosis with activation of caspase 3 or 7 in both BC31 and RT4 cells. Interestingly, tumor growth of BC31 cells subcutaneously transplanted in nude mice was significantly caused the induction of apoptosis, as well as inhibition of angiogenesis and SqD by GPX2 down-regulation. Our findings demonstrated that GPX2 plays an important role in bladder carcinogenesis through the regulation of apoptosis against intracellular ROS, and may be considered as a novel biomarker or therapeutic target in bladder cancer.
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