Novel ZEB1 expression in bladder tumorigenesis
Novel ZEB1 expression in bladder tumorigenesis
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DOI：
10.1111/j.1464-410x.2010.09489.x
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发表时间：
2011-02-01
影响因子：
4.5
通讯作者：
Summerhayes, Ian C.
中科院分区：
文献类型：
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作者：
Kenney, Patrick A.;Wszolek, Matthew F.;Summerhayes, Ian C.
上皮-间充质转化(EMT)参与了肿瘤的发展，与EMT相关的潜在细胞变化已在体外模型中确定，并在有限数量的体内研究中得到证实。ZEB1以E-钙粘素抑制为靶点，是一种转录调节因子，与EMT有关，与子宫癌和结直肠癌有关。ZEB1表达的调节已被证明涉及不同的microRNAs(MiRNAs)，确定了miRNA在EMT中的潜在作用。在本研究中，我们发现了ZEB1在膀胱肿瘤中的新表达，并在体外实验中显示了ZEB1在增强迁移和侵袭潜力中的作用。目的探讨ZEB1转录因子在膀胱肿瘤发生中的作用，明确ZEB1转录因子在膀胱尿路上皮癌(UCBS)中的可能作用。材料和方法将5 58个样本组装成10个组织芯片(TMAS；263个非肌肉侵袭性Ta/T1/Tis，295个肌肉侵袭性T2-T4)。所有肿瘤都是移行细胞癌(TCC)，并进行免疫组织化学处理以评估核ZEB1的表达。膀胱癌细胞株CUBIII和UM-UC-3在强迫表达或shRNA被敲除后，ZEB1的表达水平分别发生了变化。结果核ZEB1在22.8%的非肌肉侵袭性UCBS和21.7%的肌肉侵袭性UCBS中表达，包括24.1%的I/II级和21.1%的III级肿瘤，在正常膀胱黏膜中不表达。未观察到肿瘤分期和分级、淋巴结受累、血管侵犯、转移和总生存期或肿瘤特异性生存期的显著相关性。在膀胱癌细胞系中，ZEB1表达的导入或下调分别表现出增强或降低的迁移和侵袭能力。ZEB1表达的改变伴随着与上皮-间充质转化(EMT)相关的事件相关的microRNA(MiRNA)表达的改变。结论本研究结果显示ZEB1在膀胱癌中的新表达与临床变化变量(包括转移和生存)没有关联。然而，体外实验显示，ZEB1基因的导入或减少分别增强或降低了膀胱细胞系的迁移和侵袭能力。ZEB1表达的调节与miR-200家族以及膀胱癌进展的替代已知预后指标的变化密切相关。
Epithelial-mesenchymal transition (EMT) is involved in tumor progression where the underlying cellular changes associated with EMT have been identified in in vitro models and confirmed in a limited number of in vivo studies. ZEB1, which targets E-cadherin repression, is a transcriptional regulator that has been implicated in EMT, and is associated with uterine and colorectal cancers. Regulation of ZEB1 expression has been shown to involve different microRNAs (miRNAs), identifying a potential role for miRNA in EMT.In the present study we have identified novel expression of ZEB1 in bladder tumours and shown a role for ZEB1 in enhanced migration and invasion potential in in vitro assays. Confirmation of ZEB1 expression in bladder tumours was shown in tissue microarrays (TMAs).OBJECTIVETo evaluate ZEB1 expression in bladder tumorigenesis and define a possible role for this transcription factor in urothelial carcinomas of the bladder (UCBs).MATERIALS and METHODSFive hundred and fifty-eight samples were assembled in 10 tissue microarrays (TMAs; 263 non-muscle-invasive Ta/T1/Tis, 295 muscle-invasive T2-T4). All tumours were transitional cell carcinomas (TCCs) and processed for immunohistochemistry to assess nuclear ZEB1 expression. Expression levels of ZEB1 were modulated in bladder carcinoma cell lines CUBIII or UM-UC-3 after forced expression or shRNA knockdown, respectively. Protein expression levels were determined using western blot analysis and transfectants were assessed for migration and invasion potential in standard in vitro assays.RESULTSNuclear ZEB1 expression was recorded in 22.8% of non-muscle-invasive UCBs and 21.7% of muscle-invasive UCBs, including 24.1% grade I/II and 21.1% grade III tumours, and absent in normal bladder mucosa. No significant correlation was observed for tumour stage and grade, nodal involvement, vascular invasion, metastasis and overall or cancer-specific survival. The introduction or knockdown of ZEB1 expression in bladder carcinoma cell lines showed enhanced or reduced migration and invasive potential, respectively. Changes in ZEB1 expression were accompanied by altered microRNA (miRNA) expression underlying events linked to epithelial-mesenchymal transition (EMT).CONCLUSIONThe results in the present study showed novel expression of ZEB1 in bladder cancer in the absence of a link to clinical variables of change, including metastasis and survival. However, in vitro assays showed enhanced or reduced migration and invasion after the introduction or reduction of ZEB1, respectively, in transfected bladder cell lines. Modulation in expression of ZEB1 was closely linked to changes in the miR-200 family along with alternative known prognostic indicators of bladder tumour progression.