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

Abstract

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.

• Authors: Shuang Liu, Feng Yin, Wenhong Fan, Shuwei Wang, Xin-ru Guo, Jian-ning Zhang, Zeng-min Tian, Ming Fan
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 31 Pg. 52 (May 31 2012) ISSN: 1756-9966 [Electronic] England
• PMID: 22650359 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Smad Proteins
• Cyclin-Dependent Kinase Inhibitor p27
• BMPR1B protein, human
• Bone Morphogenetic Protein Receptors, Type I

Topics

• Animals
• Bone Morphogenetic Protein Receptors, Type I (biosynthesis, genetics)
• Brain Neoplasms (genetics, metabolism, pathology)
• Cell Cycle (physiology)
• Cell Differentiation (physiology)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis, genetics, metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (biosynthesis, genetics, metabolism)
• Female
• Gene Knockdown Techniques
• Glioblastoma (genetics, metabolism, pathology)
• Humans
• Immunohistochemistry
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Signal Transduction
• Smad Proteins (biosynthesis, genetics)
• Transfection
• Transplantation, Heterologous
• Up-Regulation