吳俊德1,4 張英勛2,4 陳文政3,4 陳妙芬3,4
基隆長庚醫院 外科部 泌尿科1 林口長庚醫院 外科部 泌尿科2
嘉義長庚醫院 放射腫瘤科3 長庚大學 醫學院4
Thrombomodulin expression regulates tumorigenesis in bladder cancer
Chun-Te Wu1,4, Ying-Hsu Chang2,4, Wen-Cheng Chen3,4 and Miao-Fen Chen3,4
Division of Urology, Chang Gung Memorial Hospital; Keelung1, Linko2, Taiwan
Division of Radiation Oncology3, Chiayi, Taiwan
School of Medicine, Chang Gung University4, Taoyuan, Taiwan
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.