Promising Prognosis Marker Candidates on the Status of Epithelial-Mesenchymal Transition and Glioma Stem Cells in Glioblastoma.

Ryuya Yamanaka,Yasuo Takashima,Atsushi Kawaguchi

doi:10.3390/cells8111312

Ryuya Yamanaka, Yasuo Takashima + Show 1 more

Open Access

https://doi.org/10.3390/cells8111312

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Journal: Cells	Publication Date: Oct 24, 2019
Citations: 24	License type: CC BY 4.0

Affiliation: Kyoto Prefectural University of Medicine, Saga University

Abstract

Multivariable analyses of global expression profiling are valid indicators of the prognosis of various diseases including brain cancers. To identify the candidates for markers of prognosis of glioblastoma, we performed multivariable analyses on the status of epithelial (EPI)–mesenchymal (MES) transition (EMT), glioma (GLI) stem cells (GSCs), molecular target therapy (MTT), and potential glioma biomarkers (PGBs) using the expression data and clinical information from patients. Random forest survival and Cox proportional hazards regression analyses indicated significant variable values for DSG3, CLDN1, CDH11, FN1, HDAC3/7, PTEN, L1CAM, OLIG2, TIMP4, IGFBP2, and GFAP. The analyses also comprised prognosis prediction formulae that could distinguish between the survival curves of the glioblastoma patients. In addition to the genes mentioned above, HDAC1, FLT1, EGFR, MGMT, PGF, STAT3, SIRT1, and GADD45A constituted complex genetic interaction networks. The calculated status scores obtained by principal component analysis indicated that GLI genes covered the status of EPI, GSC, and MTT-related genes. Moreover, survival tree analyses indicated that MEShigh, MEShighGLIlow, GSChighGLIlow, MEShighMTTlow, and PGBhigh showed poor prognoses and MESmiddle, GSClow, and PGBlow showed good prognoses, suggesting that enhanced EMT and GSC are associated with poor survival and that lower expression of EPI markers and the pre-stages of EMT are relatively less malignant in glioblastoma. These results demonstrate that the assessment of EMT and GSC enables the prediction of the prognosis of glioblastoma that would help develop novel therapeutics and de novo marker candidates for the prognoses of glioblastoma.

Highlights

The World Health Organization (WHO) classifies gliomas into four categories based on malignancy and overall survival (OS) [1]
Are associated with poor survival and that lower expression of EPI markers and the pre-stages of EMT are relatively less malignant in glioblastoma. These results demonstrate that the assessment of EMT and glioma stem cells (GSCs) enables the prediction of the prognosis of glioblastoma that would help develop novel therapeutics and de novo marker candidates for the prognoses of glioblastoma
The aim of this study is to identify promising prognosis marker candidates of glioblastoma

Summary

Introduction

The World Health Organization (WHO) classifies gliomas into four categories based on malignancy and overall survival (OS) [1]. Glioblastoma is the most malignant form of astrocytoma that is fast-growing (grade 4 glioma) [1,2]. The median OS of glioblastoma is 9–15 months and the five-year survival rate remains less than 5% [1,3,4,5]. Radiotherapy with six cycles of concomitant temozolomide, an oral alkylating agent with minimal additional toxicity, is the standard treatment after surgery in glioblastoma patients [2,4,5]. There is an immediate requirement for the early diagnosis and precise prediction of the prognosis for treatments of glioblastoma. Glioma cells are reprogrammed to have increased motility via weakened cell adhesions and a dysregulated cytoskeleton; this is known as epithelial–mesenchymal

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