Small G protein Rac GTPases regulate the maintenance of glioblastoma stem-like cells in vitro and in vivo
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Yun-Ju Lai1, Jui-Cheng Tsai1, Ying-Ting Tseng1, Meng-Shih Wu1, Wen-Shan Liu1, Hoi-Ian Lam1, Jei-Hwa Yu3, Susan E. Nozell2, Etty N. Benveniste2
1Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
2Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, AL, USA
3Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, AL, USA
Yun-Ju Lai, email: email@example.com
Etty N. Benveniste, email: firstname.lastname@example.org
Keywords: glioblastoma, Rac small G protein, glioblastoma-initiating cells, cancer stem cells, zebrafish xenotransplantation
Received: January 21, 2016 Accepted: January 03, 2017 Published: February 01, 2017
Glioblastoma is the most common and aggressive malignant brain tumor in adults. The existence of glioblastoma stem cells (GSCs) or stem–like cells (stemloids) may account for its invasiveness and high recurrence. Rac proteins belong to the Rho small GTPase subfamily which regulates cell movement, proliferation, and survival. To investigate whether Rac proteins can serve as therapeutic targets for glioblastoma, especially for GSCs or stemloids, we examined the potential roles of Rac1, Rac2 and Rac3 on the properties of tumorspheres derived from glioblastoma cell lines. Tumorspheres are thought to be glioblastoma stem-like cells. We showed that Rac proteins promote the STAT3 and ERK activation and enhance cell proliferation and colony formation of glioblastoma stem-like cells. Knockdown of Rac proteins reduces the expression of GSC markers, such as CD133 and Sox2. The in vivo effects of Rac proteins in glioblastoma were further studied in zebrafish and in the mouse xenotransplantation model. Knocking-down Rac proteins abolished the angiogenesis effect induced by the injected tumorspheres in zebrafish model. In the CD133+-U373-tumorsphere xenotransplanted mouse model, suppression of Rac proteins decreased the incidence of tumor formation and inhibited the tumor growth. Moreover, knockdown of Rac proteins reduced the sphere forming efficiency of cells derived from these tumors. In conclusion, not only Rac1 but also Rac2 and 3 are important for glioblastoma tumorigenesis and can serve as the potential therapeutic targets against glioblastoma and its stem-like cells.
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