Osteoglycin promotes meningioma development through downregulation of NF2 and activation of mTOR signaling

Cell Communication and Signaling

Research

Yu Mei¹  Ian F. Dunn¹  Nathalie Y.R. Agar²  Noah F. Greenwald²  Wenya Linda Bi²  Changchen Hu³  Gavin P. Dunn⁴  Sandro Santagata⁵  Ziming Du⁵  Malak Abedalthagafi⁶ 

[1] Center for Skull Base and Pituitary Surgery, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA;Center for Skull Base and Pituitary Surgery, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA;Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;Center for Skull Base and Pituitary Surgery, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA;Department of Neurosurgery, Shanxi Provincial People’s Hospital, Shanxi Medical University, Taiyuan, China;Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, USA;Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA;Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA;Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA;Saudi Human Genome Laboratory, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia;

关键词: Osteoglycin;    Autophagy;    AKT inhibitor;    Meningioma;    Neurofibromatosis type 2;    Mammalian target of rapamycin complex 1;   

DOI  :  10.1186/s12964-017-0189-7

 received in 2017-05-03, accepted in 2017-09-01,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundMeningiomas are the most common primary intracranial tumors in adults. While a majority of meningiomas are slow growing neoplasms that may cured by surgical resection, a subset demonstrates more aggressive behavior and insidiously recurs despite surgery and radiation, without effective alternative treatment options. Elucidation of critical mitogenic pathways in meningioma oncogenesis may offer new therapeutic strategies. We performed an integrated genomic and molecular analysis to characterize the expression and function of osteoglycin (OGN) in meningiomas and explored possible therapeutic approaches for OGN-expressing meningiomas.MethodsOGN mRNA expression in human meningiomas was assessed by RNA microarray and RNAscope. The impact of OGN on cell proliferation, colony formation, and mitogenic signaling cascades was assessed in a human meningioma cell line (IOMM-Lee) with stable overexpression of OGN. Furthermore, the functional consequences of introducing an AKT inhibitor in OGN-overexpressing meningioma cells were assessed.ResultsOGN mRNA expression was dramatically increased in meningiomas compared to a spectrum of other brain tumors and normal brain. OGN-overexpressing meningioma cells demonstrated an elevated rate of cell proliferation, cell cycle activation, and colony formation as compared with cells transfected with control vector. In addition, NF2 mRNA and protein expression were both attenuated in OGN-overexpressing cells. Conversely, mTOR pathway and AKT activation increased in OGN-overexpressing cells compared to control cells. Lastly, introduction of an AKT inhibitor reduced OGN expression in meningioma cells and resulted in increased cell death and autophagy, suggestive of a reciprocal relationship between OGN and AKT.ConclusionWe identify OGN as a novel oncogene in meningioma proliferation. AKT inhibition reduces OGN protein levels in meningioma cells, with a concomitant increase in cell death, which provides a promising treatment option for meningiomas with OGN overexpression.

【 授权许可】

CC BY   
© The Author(s). 2017