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  • Urothelium covers the epithelial lining of the urinary tract from the renal calyces to the bladder. Any neoplastic lesion grew from the urothelium has similar behavior[pone.0082804-Sagalowsky1]. The most frequent malignant tumor of urinary tract is urothelial cell carcinoma (UCC). In the United State, bladder cancer is the fourth most common cancer among men [pone.0082804-Jacobs1] and bladder cancer is the second most genitourinary cancer. In Taiwan, bladder cancer is the ninth leading malignancy among men and the sixteenth leading malignancy among women [pone.0082804-Health1]. UCC composed more than 90% of bladder cancer in both genders. The incidence of upper urinary tract UCC is also increasing. The most known risk factors are tobacco use and aromatic amines exposure [pone.0082804-Colin1]–[pone.0082804-Rouissi1]. However, many articles emphasized the importance of genetic factors in the development of UCC [pone.0082804-Wang3]. Genetic variation affects the function of oncogene, tumor suppressor gene or metabolism of enzyme to induce cancer formation. Hypoxia is the common cause of tumor [pone.0082804-Vaupel1]. Decreased O2 concentration created a hostile metabolic microenvironment (e.g., existence of severe tissue acidosis) to activate a variety of biological responses including signal pathways of proliferation, angiogenesis and death [pone.0082804-Vaupel1]. Tumor cells can survive and even grow under hypoxic condition. Tumor hypoxia is associated with aggressive tumor growth, metastasis, and treatment failure after radiation therapy and chemotherapy [pone.0082804-Harris1]. Hypoxia might be an important therapeutic target because it involved many different metabolic pathways in cancer growth.

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