TY - JOUR
T1 - Kinome and phosphoproteome of high-grade meningiomas reveal AKAP12 as a central regulator of aggressiveness and its possible role in progression
AU - Parada, Carolina Angelica
AU - Osbun, Joshua
AU - Kaur, Sumanpreet
AU - Yakkioui, Youssef
AU - Shi, Min
AU - Pan, Catherine
AU - Busald, Tina
AU - Karasozen, Yigit
AU - Gonzalez-Cuyar, Luis Francisco
AU - Rostomily, Robert
AU - Zhang, Jing
AU - Ferreira, Manuel
N1 - Funding Information:
The authors thank Dr. Michael O. Dorschner (University of Washington, Seattle, WA) for sequencing; Jason Baber (University of Washington, Seattle, WA) for statistics and Donna Prunkard (University of Washington, Seattle, WA) for flow cytometry analysis. Kathi Goertzen Foundation provided financial support. Dr. Robert Rostomily is now at the Department of Neurosurgery, Houston Methodist Hospital and Research Institute.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/2/1
Y1 - 2018/2/1
N2 - There is a need to better understand meningioma oncogenesis for biomarker discovery and development of targeted therapies. Histological or genetic criteria do not accurately predict aggressiveness. Post-translational studies in meningioma progression are lacking. In the present work, we introduce a combination of mass spectrometry-based phosphoproteomics and peptide array kinomics to profile atypical and anaplastic (high-grade) meningiomas. In the discovery set of fresh-frozen tissue specimens (14), the A-kinase anchor protein 12 (AKAP12) protein was found downregulated across the grades. AKAP12 knockdown in benign meningioma cells SF4433 increases proliferation, cell cycle, migration, invasion, and confers an anaplastic profile. Differentially regulated pathways were characteristic of high-grade meningiomas. Low AKAP12 expression in a larger cohort of patients (75) characterized tumor invasiveness, recurrence, and progression, indicating its potential as a prognostic biomarker. These results demonstrate AKAP12 as a central regulator of meningioma aggressiveness with a possible role in progression.
AB - There is a need to better understand meningioma oncogenesis for biomarker discovery and development of targeted therapies. Histological or genetic criteria do not accurately predict aggressiveness. Post-translational studies in meningioma progression are lacking. In the present work, we introduce a combination of mass spectrometry-based phosphoproteomics and peptide array kinomics to profile atypical and anaplastic (high-grade) meningiomas. In the discovery set of fresh-frozen tissue specimens (14), the A-kinase anchor protein 12 (AKAP12) protein was found downregulated across the grades. AKAP12 knockdown in benign meningioma cells SF4433 increases proliferation, cell cycle, migration, invasion, and confers an anaplastic profile. Differentially regulated pathways were characteristic of high-grade meningiomas. Low AKAP12 expression in a larger cohort of patients (75) characterized tumor invasiveness, recurrence, and progression, indicating its potential as a prognostic biomarker. These results demonstrate AKAP12 as a central regulator of meningioma aggressiveness with a possible role in progression.
KW - A Kinase Anchor Proteins/metabolism
KW - Biomarkers, Tumor/metabolism
KW - Carcinogenesis
KW - Cell Cycle
KW - Cell Cycle Proteins/metabolism
KW - Cell Movement
KW - Cell Proliferation
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Male
KW - Meningeal Neoplasms/metabolism
KW - Meningioma/metabolism
KW - Middle Aged
KW - Neoplasm Invasiveness
KW - Neoplasm Recurrence, Local/metabolism
KW - Phosphoproteins/metabolism
KW - Prognosis
KW - Protein Kinases/metabolism
KW - Proteome/analysis
KW - Survival Rate
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U2 - 10.1038/s41598-018-19308-y
DO - 10.1038/s41598-018-19308-y
M3 - Article
C2 - 29391485
AN - SCOPUS:85041634512
VL - 8
SP - 2098
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 2098
ER -