Abstract
BackgroundIn 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.MethodsWe 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 conclusionForced 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.
Highlights
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
We found that the mRNA expression of BMPR-IB mRNA in all glioblastoma cell lines decreased compared to normal astrocytes, while the expression of the other genes remained similar between normal astrocytes and malignant glioma cell lines (Figure 1A)
The protein expression of BMPR-IB and phospho-Smad1/5/8 in all malignant glioma cell lines was lower than the levels in normal astrocytes; intracellular protein expression of BMPR-IB was moderately lower in SF763 cells and drastically lower in other malignant glioma cell lines compared to normal astrocytes (Figure 1B)
Summary
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. Advances in the treatment of malignant gliomas will require improved understanding of the biology and molecular mechanisms of glioma development and progression. Many studies show that the malignant transformation of glioma is a consequence of the stepwise accumulation of genetic alterations that lead to aberrant regulation of proliferation and differentiation signals and disruption of the apoptotic pathway [1]. Recent research on the molecular basis of gliomas and the implications for targeted therapeutics has focused on the PTEN, EGFR and VEGF signaling pathways [2,3,4]. These pathways, while important, represent only a subset of the multiple molecular mediators of glioma tumorigenesis and malignancy [1]
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