Carbonic anhydrase 2 is a novel invasion-associated factor in urinary bladder cancers.
Carbonic anhydrase 2 is a novel invasion-associated factor in urinary bladder cancers.
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DOI：
10.1111/cas.13143
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发表时间：
2017-03
期刊：
影响因子：
5.7
通讯作者：
Wanibuchi H
中科院分区：
文献类型：
--
作者：
Tachibana H;Gi M;Kato M;Yamano S;Fujioka M;Kakehashi A;Hirayama Y;Koyama Y;Tamada S;Nakatani T;Wanibuchi H
大鼠膀胱癌几乎总是乳头状非浸润性尿路上皮癌（UC）。为了建立一种模拟膀胱中乳头状非侵袭性UC引起的侵袭性UC的动物模型，用0.05% N-丁基-N-甲基-N-（2-甲基-N-苯基）-N-（2-甲基-（羟丁基）亚硝胺（BBN）和/或0.1%苯乙基异硫氰酸酯（PEITC）在其饮食中的作用如下：BBN（8周）→PEITC（8周）; PEITC（8周）→BBN（8周）;单独使用BBN（16周）;单独使用PEITC（16周）;并且不进行治疗。在第16周结束时，在BBN→PEITC组中观察到浸润性UC的发生率最高。因此，我们使用用BBN随后用PEITC处理的Hras 128大鼠作为侵袭性膀胱癌模型来鉴定侵袭相关蛋白。进行蛋白质组分析以比较Hras 128大鼠中侵袭性和非侵袭性UC的蛋白质谱。我们确定了49种蛋白质在侵袭性UC中过表达或表达不足，但在非侵袭性UC中没有。碳酸酐酶2（CA 2）（一种过表达蛋白）的免疫组织化学分析显示，大鼠中侵袭性UC的CA 2阳性UC的相对数量显著高于非侵袭性UC。此外，与非MIBC（NMIBC）相比，人类肌肉浸润性膀胱癌（MIBC）的CA 2阳性癌症发生率也显著更高，并且与NMIBC的进展呈正相关。我们的研究结果表明，CA 2是一种侵袭相关因子，并表明它可以作为膀胱癌的潜在治疗分子靶点。
Rat bladder cancer is nearly always papillary non‐invasive urothelial carcinoma (UC). To establish an animal model mimicking invasive UC that arises from papillary non‐invasive UC in the bladder, male human c‐Ha‐ras proto‐oncogene transgenic rats (Hras128) were treated with 0.05% N‐butyl‐N‐(hydroxybutyl)nitrosameine (BBN) in their drinking water and/or 0.1% phenylethyl isothiocyanate (PEITC) in their diet as follows: BBN (8 weeks)→PEITC (8 weeks); PEITC (8 weeks)→BBN (8 weeks); BBN alone (16 weeks); PEITC alone (16 weeks); and no treatment. At the end of week 16, the highest incidence of invasive UC was observed in the BBN→PEITC group. Therefore, we used Hras128 rats treated with BBN followed by PEITC as a model of invasive bladder cancer to identify invasion‐associated proteins. Proteome analysis was performed to compare the protein profiles of invasive and non‐invasive UC in Hras128 rats. We identified 49 proteins that were either overexpressed or underexpressed in invasive UC but not in non‐invasive UC. Immunohistochemical analysis of carbonic anhydrase 2 (CA2), an overexpressed protein, showed that the relative number of CA2‐positive UC was significantly higher for invasive UC compared to non‐invasive UC in rats. Moreover, the incidence of CA2‐positive cancers was also significantly higher for human muscle‐invasive bladder cancer (MIBC) compared to non‐MIBC (NMIBC) and was positively associated with the progression of NMIBC. Our findings indicate that CA2 is an invasion‐associated factor and suggest that it could serve as a potential therapeutic molecular target for bladder cancers.