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Open Access Highly Accessed Research article

Thrombomodulin expression regulates tumorigenesis in bladder cancer

Chun-Te Wu12, Ying-Hsu Chang23, Paul- Yang Lin24, Wen-Cheng Chen25 and Miao-Fen Chen25*

Author Affiliations

1 Department of Urology, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan

2 Chang Gung University, College of medicine, Taoyuan, Taiwan

3 Department of Urology, Chang Gung Memorial Hospital at Linko, Linko, Taiwan

4 Department of Pathology, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan

5 Radiation Oncology, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan

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BMC Cancer 2014, 14:375  doi:10.1186/1471-2407-14-375

Published: 28 May 2014

Abstract

Background

The identification of potential tumor markers will help improve therapeutic planning and patient management. Thrombomodulin (TM) is a sensitive urothelial marker. TM was reported to be one of the endogenous anti-metastatic factors and has diagnostic and prognostic values for the progression of carcinoma. In the present study, we examine the role of TM in bladder cancer.

Methods

We studied the role of TM in tumor behavior and related signaling pathways in vitro using the human bladder cancer cell lines HT1376, HT1197, J82 and T24, and in vivo using animal models. We also selected clinical specimens from 100 patients with bladder cancer for immunohistochemical staining to evaluate the predictive capacity of TM in tumor invasiveness.

Results

The data revealed that positive immunoreactivity for TM was inversely correlated with clinical stage and DNA methyltransferase 1 immunoreactivity. Decreased TM expression could predict the aggressive tumor growth and advanced clinical stage in bladder cancer. When TM was inhibited, tumor growth rate and invasion ability were augmented in vitro and in vivo. The underlying changes included increased cell proliferation, enhanced epithelial-mesenchymal transition (EMT) and angiogenesis. Moreover, inhibition of NF-κB activation significantly increased TM expression and attenuated tumor aggressiveness in bladder cancer.

Conclusions

TM plays an important role in bladder cancer tumor aggressiveness in vitro and in vivo and is a clinically significant predictor that may represent a suitable therapeutic target for bladder cancer.

Keywords:
Bladder cancer; Thrombomodulin; DNMT1; Epithelial-mesenchymal transition (EMT)