Novel ZEB1 expression in bladder tumorigenesis

Abstract

What’s known on the subject? and What does the study add? 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). OBJECTIVE To evaluate ZEB1 expression in bladder tumorigenesis and define a possible role for this transcription factor in urothelial carcinomas of the bladder (UCBs). MATERIALS and METHODS Five 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. RESULTS Nuclear 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). CONCLUSION The 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.

The evolving understanding of microRNA in bladder cancer

“…Therefore, this transcription factor may globally repress the miR-200 family rather than individual members. In addition to its potential effects on Twist, increased miR-200c expression correlates with reduced migration and invasion of invasive BC cell lines and loss of ZEB-1 expression, consistent with the role of ZEB-1 in promoting mesenchymal differentiation [54]. …”

ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1

“…Overexpression of ZEB1 has been observed in human breast tumors 57, 58 and other cancer types 59, 60 . Our findings raise the caution that radiation treatment may lead to upregulation of ZEB1 and therapy-induced radioresistance.…”

Vasculogenic mimicry in bladder cancer and its association with the aberrant expression of ZEB1

“…Similarly, ZEB2, a homologous protein of ZEB1, was found to have the same function in inducing EMT, promoting VM formation in hepatocellular carcinoma (17). Although there is no consensus about the correlation between ZEB1 expression and tumor grade, stage, invasion and metastasis in bladder cancer, numerous studies have verified that ZEB1 is significantly overexpressed in bladder cancer tissues in comparison with healthy adjacent tissues (18)(19)(20). However, it has not been reported whether ZEB1 plays a critical role in VM formation in bladder cancer.…”