The role of Sry-related HMG Box-4 (SOX4) in bladder cancer and cancer stem-ness
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Bladder cancer is the seventh most common form of cancer worldwide and the second most common urologic malignancy. It consists of the non-muscle invasive and muscle invasive form, of which the latter often becomes metastatic with a poor 5 year survival rate of only 5%. Hence, the identification of new diagnostic or therapeutic targets in muscle invasive bladder cancer is crucial. From TCGA data analysis, it appeared that SOX4 is frequently upregulated in invasive bladder cancer. SOX4 was found to mediate tumorigenesis and tumor progression, indicating a function as oncogene. On the other hand, it was also linked to tumor suppressive processes; dependent on the tumor type, tumor stage and cellular context. In the first part of this project, we demonstrate that knock down of SOX4 significantly decreases cell migration capacity, anchorage independent growth in soft agar, self-renewal potential in muscle invasive bladder cancer RT-112 cells and dramatically inhibits its tumorigenesis in vivo. These results indicate an oncogenic role of SOX4 in muscle invasive bladder cancer, possibly through the expansion of cancer stem cells (CSCs). In the second part of this project, the applicability of the CSC marker ALDH is assessed in a panel of bladder cancer cell lines. The stem-like properties of ALDH high versus ALDH low populations are assessed using the in vitro sphere forming assay and in vivo xenotransplantation in serial dilutions. We showed that there is no positive correlation between ALDH high population and the self-renewal potential. Bladder spheres formed from RT-112 cells contain a heterogeneous ALDH population. In addition, RT-112 bladder cancer cells were sorted into ALDH high and ALDH low populations. Both populations showed self-renewal potential and were capable of heterogeneous lineage formation. After injection of as few as 100 cells, both populations initiated tumor growth in mice. These findings indicate that the ALDH high phenotype is not a suitable CSC marker in bladder cancer.