SOX2-Mediated Oncogenesis and Its Crosstalk with Environmental Risk Factors in Bladder Cancer

Several environmental risk factors, such as chronic arsenic exposure and cigarette smoking, have been shown to correlate with bladder cancer formation. Recently, the hypothesis of cancer stem cell, highlighting the involvement of stem cell signaling in oncogenesis, has received substantial interest and supports. However, how environment risk factors crosstalk with stem cell signaling to shape the formation of cancer stem cells, hence affecting cancer progression, is little appreciated. During the course of study, I have observed that, SOX2 (SRY (sex determining region Y)-box 2), a master transcriptional factor involved in self-renewal and pluripotency of several stem cells, is highly expressed in a subgroup of bladder cancer cells. Moreover, the proliferation of these bladder cancer cells is dependent on SOX2 signaling. Through immunohistochemisty analysis, I found that SOX2 is predominantly expressed in transitional cell carcinoma, the grades of which are correlated with SOX2 levels. These findings support a critical involvement of SOX2 in bladder cancer initiation and progression. Thus, to explore the functional roles of SOX2 and its crosstalk with environment factors on bladder cancer initiation and progression, four specific aims are proposed. First, I plan to measure the SOX2 levels and correlate its expression with clinicopathological features, such as TNM stages, recurrence, metastasis and survival in bladder cancer. Second, I plan to carry out gene and miRNA profiling to identify novel therapeutic targets and biomarkers involved in SOX2-mediated cancer stemness. Third, I plan to perform correlation analysis of SOX2 expression with environmental factors, such as cigarette smoking and chronic arsenic exposure in patients with bladder cancer. Fourth, I conduct a case-control study to investigate the interaction between genetic polymorphisms of SOX2-related genes and environment risk factors on the prognosis of bladder cancer. Successful accomplishment of this project may bring new insights into future prognosis and treatment of bladder cancer.