Bo Wang1,2, Chen Cao3, Xi Liu4, Xin He5, Hao Zhuang6, Dong Wang7, Budong Chen8. 1. Department of Neurosurgery, Tianjin Huanhu Hospital; Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative diseases, Tianjin Neurosurgical Institute, No. 6 Jizhao Road, Tianjin, 300350, China. 2. State Key Laboratory of Medicinal Chemical Biology, Nankai University, No.94 Weijin Road, Tianjin, 300071, China. 3. Department of Medical Imaging, Tianjin Huanhu Hospital; Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative diseases, Tianjin Neurosurgical Institute, No. 6 Jizhao Road, Tianjin, 300350, China. 4. Department of Gastroenterology, Tianjin Nankai Hospital, No.6 Changjiang Road, Tianjin, 300100, China. 5. Department of Biological Sciences, Virginia Tech, Blacksburg, VA, 24061, USA. 6. Department of Hepatic Biliary Pancreatic Surgery, Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou, 450008, Henan Province, China. zhh8764@163.com. 7. Department of Neurosurgery, General Hospital; Tianjin Key Laboratory of Injuries, Variations, and Regeneration of Nervous System; Tianjin Neurological Institute, Tianjin Medical University, No.154 Anshan Road, Tianjin, 300052, China. 54454241@qq.com. 8. Department of Neurosurgery, Tianjin Huanhu Hospital; Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative diseases, Tianjin Neurosurgical Institute, No. 6 Jizhao Road, Tianjin, 300350, China. cbdgby@163.com.
Abstract
PURPOSE: BRCA1-associated protein (BRAP) was first identified by its ability to bind to the nuclear localization signalling motif of BRCA1 and other proteins. Subsequently, human BRAP has been found to exert multiple functions, many of which are related to cancer development. Up till now, however, the role of BRAP in glioma development has remained obscure. Here, we report a role for BRAP in mediating the proliferation and migration of glioma cells both in vitro and in vivo. METHODS: The expression of BRAP in 98 glioma patient samples was determined by immunohistochemistry, after which associations between BRAP expression and patient prognosis were assessed. A short hairpin RNA (shRNA) was used to knock down BRAP and an expression vector was used to exogenously overexpress BRAP in glioma cells. The effects of BRAP expression on tumour cell behaviour in vitro and in an in vivo xenograft mouse model were examined. RESULTS: We found that in glioma patients BRAP expression was associated with a favourable prognosis. We also found that shRNA-mediated knockdown of BRAP facilitated the proliferation and migration of glioma cells and the self-renewal of glioma stem cells. In parallel, we found that BRAP knockdown increased tumour growth and invasion and decreased survival in an in vivo glioma xenograft mouse model. Mechanistically, we found that BRAP inhibited glioma cell proliferation and migration, as well as glioma stem cell self-renewal via the TGF-β/PI3K/AKT/mTOR signalling pathway. CONCLUSIONS: Together, our findings identify BRAP as a mediator of glioma cell proliferation, migration and glioma stem cell self-renewal.
PURPOSE:BRCA1-associated protein (BRAP) was first identified by its ability to bind to the nuclear localization signalling motif of BRCA1 and other proteins. Subsequently, humanBRAP has been found to exert multiple functions, many of which are related to cancer development. Up till now, however, the role of BRAP in glioma development has remained obscure. Here, we report a role for BRAP in mediating the proliferation and migration of glioma cells both in vitro and in vivo. METHODS: The expression of BRAP in 98 gliomapatient samples was determined by immunohistochemistry, after which associations between BRAP expression and patient prognosis were assessed. A short hairpin RNA (shRNA) was used to knock down BRAP and an expression vector was used to exogenously overexpress BRAP in glioma cells. The effects of BRAP expression on tumour cell behaviour in vitro and in an in vivo xenograft mouse model were examined. RESULTS: We found that in gliomapatientsBRAP expression was associated with a favourable prognosis. We also found that shRNA-mediated knockdown of BRAP facilitated the proliferation and migration of glioma cells and the self-renewal of glioma stem cells. In parallel, we found that BRAP knockdown increased tumour growth and invasion and decreased survival in an in vivo glioma xenograft mouse model. Mechanistically, we found that BRAP inhibited glioma cell proliferation and migration, as well as glioma stem cell self-renewal via the TGF-β/PI3K/AKT/mTOR signalling pathway. CONCLUSIONS: Together, our findings identify BRAP as a mediator of glioma cell proliferation, migration and glioma stem cell self-renewal.
Authors: Fredrick R Schumacher; Stephanie L Schmit; Shuo Jiao; Christopher K Edlund; Hansong Wang; Ben Zhang; Li Hsu; Shu-Chen Huang; Christopher P Fischer; John F Harju; Gregory E Idos; Flavio Lejbkowicz; Frank J Manion; Kevin McDonnell; Caroline E McNeil; Marilena Melas; Hedy S Rennert; Wei Shi; Duncan C Thomas; David J Van Den Berg; Carolyn M Hutter; Aaron K Aragaki; Katja Butterbach; Bette J Caan; Christopher S Carlson; Stephen J Chanock; Keith R Curtis; Charles S Fuchs; Manish Gala; Edward L Giovannucci; Stephanie M Gogarten; Richard B Hayes; Brian Henderson; David J Hunter; Rebecca D Jackson; Laurence N Kolonel; Charles Kooperberg; Sébastien Küry; Andrea LaCroix; Cathy C Laurie; Cecelia A Laurie; Mathieu Lemire; David Levine; Jing Ma; Karen W Makar; Conghui Qu; Darin Taverna; Cornelia M Ulrich; Kana Wu; Suminori Kono; Dee W West; Sonja I Berndt; Stéphane Bezieau; Hermann Brenner; Peter T Campbell; Andrew T Chan; Jenny Chang-Claude; Gerhard A Coetzee; David V Conti; David Duggan; Jane C Figueiredo; Barbara K Fortini; Steven J Gallinger; W James Gauderman; Graham Giles; Roger Green; Robert Haile; Tabitha A Harrison; Michael Hoffmeister; John L Hopper; Thomas J Hudson; Eric Jacobs; Motoki Iwasaki; Sun Ha Jee; Mark Jenkins; Wei-Hua Jia; Amit Joshi; Li Li; Noralene M Lindor; Keitaro Matsuo; Victor Moreno; Bhramar Mukherjee; Polly A Newcomb; John D Potter; Leon Raskin; Gad Rennert; Stephanie Rosse; Gianluca Severi; Robert E Schoen; Daniela Seminara; Xiao-Ou Shu; Martha L Slattery; Shoichiro Tsugane; Emily White; Yong-Bing Xiang; Brent W Zanke; Wei Zheng; Loic Le Marchand; Graham Casey; Stephen B Gruber; Ulrike Peters Journal: Nat Commun Date: 2015-07-07 Impact factor: 14.919