GPX2 promotes development of bladder cancer with squamous cell differentiation through the control of apoptosis.
GPX2 promotes development of bladder cancer with squamous cell differentiation through the control of apoptosis.
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DOI：
10.18632/oncotarget.24627
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发表时间：
2018-03-23
期刊：
影响因子：
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通讯作者：
Takahashi S
中科院分区：
文献类型：
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作者：
Naiki T;Naiki-Ito A;Iida K;Etani T;Kato H;Suzuki S;Yamashita Y;Kawai N;Yasui T;Takahashi S
在此，我们阐明了谷胱甘肽过氧化物酶2 （GPX2）在膀胱癌中的分子机制和治疗潜力。在n -丁基- n -（4-羟基丁基）亚硝胺（BBN）诱导的大鼠膀胱癌模型中，GPX2的表达在从正常到乳头状或结节性增生（PNHP）和尿路上皮癌（UC）的进展过程中逐渐升高。GPX2过表达在UC鳞状分化（SqD）中比在单纯UC中更为明显。乳头状UC和侵袭性UC伴SqD的临床上皮内病变在人类根治性膀胱切除术标本中也有很强的GPX2表达。此外，经尿道标本的预后分析显示，GPX2的低表达水平预示着纯UC患者的预后不良。此外，体外培养的UC细胞系BC31和RT4也过表达GPX2。在BC31和RT4细胞中，GPX2的敲除引起细胞内活性氧（ROS）产生的显著抑制，以及显著的生长抑制和caspase 3或7的激活导致细胞凋亡增加。有趣的是，裸鼠皮下移植BC31细胞的肿瘤生长明显诱导凋亡，GPX2下调抑制血管生成和SqD。我们的研究结果表明，GPX2通过调控细胞凋亡对抗细胞内ROS在膀胱癌发生中发挥重要作用，可能成为膀胱癌新的生物标志物或治疗靶点。
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.