Over-expression of BMPR-IB reduces the malignancy of glioblastoma cells by upregulation of p21 and p27Kip1

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• 作者：Shuang Liu (1) (2)
  Feng Yin (1)
  Wenhong Fan (2)
  Shuwei Wang (1)
  Xin-ru Guo (1)
  Jian-ning Zhang (1)
  Zeng-min Tian (1)
  Ming Fan (2) (3)
  
• 关键词：1. BMPR ; IB ; 2. Glioblastoma ; 3. Growth inhibition ; 4. Differentiation
• 刊名：Journal of Experimental & Clinical Cancer Research
• 出版年：2012
• 出版时间：December 2012
• 年：2012
• 卷：31
• 期：1
• 全文大小：1525KB
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• 作者单位：Shuang Liu (1) (2)
  Feng Yin (1)
  Wenhong Fan (2)
  Shuwei Wang (1)
  Xin-ru Guo (1)
  Jian-ning Zhang (1)
  Zeng-min Tian (1)
  Ming Fan (2) (3)
  
  1. Department of Neurosurgery, Navy General Hospital, 100048, Beijing, China
  2. Department of Brain Protection & Plasticity Research, Beijing Institute of Basic Medical Sciences, Taiping Road 27, Beijing, 100850, People鈥檚 Republic of China
  3. Beijing Institute Neuroscience, Capital Medical University, Beijing, 100069, China
  
• ISSN：1756-9966

文摘

Background In our previous study, we detected decreased expression of phospho-Smad1/5/8 and its upstream signaling molecule, bone morphogenetic protein receptor IB subunit (BMPR-IB), in certain glioblastoma tissues, unlike normal brain tissues. In order to clarify the functional roles and mechanism of BMPR-IB in the development of glioblastoma, we studied the effects of BMPR-IB overexpression on glioblastoma cell lines in vitro and in vivo. Methods We selected glioblastoma cell lines U251, U87, SF763, which have different expression of BMPR-IB to be the research subjects. Colony formation analysis and FACS were used to detect the effects of BMPR-IB on the growth and proliferation of glioblastoma cells in vivo. Immunofluresence was used to detect the differentiation changes after BMPR-IB overexpression or knocking-down. Then we used subcutaneous and intracranial tumor models to study the effect of BMPR-IB on the growth and differentiation of glioblastoma cells in vivo. The genetic alterations involved in this process were examined by real-time PCR and western blot analysis.ed. Results and conclusion Forced BMPR-IB expression in malignant human glioma cells, which exhibit lower expression of BMPR-IB, induced the phosphorylation and nuclear localization of smad1/5/8 and arrested the cell cycle in G1. Additionally, BMPR-IB overexpression could suppress anchorage-independent growth and promote differentiation of theses glioblastoma cells. Furthermore, overexpression of BMPR-IB inhibited the growth of subcutaneous and intracranial tumor xenografts and prolonged the survival of mice injected intracranially with BMPR-IB-overexpressing glioblastoma cells. Conversely, inhibition of BMPR-IB caused SF763 malignant glioma cells, a line known to exhibit high BMPR-IB expression that does not form tumors when used for xenografts, to show increased growth and regain tumorigenicity in a nude mouse model system, ultimately shortening the survival of these mice. We also observed significant accumulation of p21 and p27kip1 proteins in response to BMPR-IB overexpression. Our study suggests that overexpression of BMPR-IB may arrest and induce the differentiation of glioblastoma cells due to upregulation of p21 and p27kip1 in vitro and that in vivo and decreased expression of BMPR-IB in human glioblastoma cells contributes to glioma tumorigenicity. BMPR-IB could represent a new potential therapeutic target for malignant human gliomas.