Abstract
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.
Highlights
Bladder cancer is the ninth most common cancer, with an estimated global incidence of 429,000 in 2012 [1], and the development of new treatment modalities is impending based on the clarification of therapeutic molecular mechanisms
We first examined the status of glutathione peroxidase 2 (GPX2), using specimens obtained from a bladder carcinogenesis model induced by treatment of rats with N-butylN-(4-hydroxybutyl) nitrosamine (BBN) and 0.05% phenylethyl isothiocyanate (PEITC)
We found by immunohistochemical analyses that the protein expression level of Gpx2 in the normal epithelium of the butyl-N-(4-hydroxybutyl) nitrosamine (BBN) + PEITC-treated group was significantly elevated as compared to that of the non-treated control group (Figure 1A-1D, 1K)
Summary
Bladder cancer is the ninth most common cancer, with an estimated global incidence of 429,000 in 2012 [1], and the development of new treatment modalities is impending based on the clarification of therapeutic molecular mechanisms. There is heightened interest in the role of oxidative stress and the status of antioxidant agents in bladder cancer [4,5,6], as well as antioxidant mechanisms that can be manipulated as therapeutic targets for cancer prevention or as prognostic biomarkers [7,8,9,10]. The glutathione redox system is the most important antioxidant agent that protects against www.oncotarget.com intracellular damage induced by oxidative stress in humans [11, 12]. Eight different isoforms of GPX have been reported in mammals [12, 13] They appear to have antioxidant function at several locations and cellular components. GPX1 is ubiquitously found in the cytosol and mitochondria of liver, lung kidney, and red blood cells, and GPX2 is mainly expressed in the cytosol of mammary tissue and the gastrointestinal tract, as well as in the human liver [11, 14, 15]
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