- Division of Neurosurgery, Department of Surgery, Changhua Christian Hospital, Changhua, China
- Graduate Institute of Life Science, National Defense Medical Center, Taipei, Taiwan, ROC
- Transplant Medicine and Surgery Research Centre, Changhua Christian Hospital, Changhua, China
- Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC
Correspondence Address:
Chien-Min Chen, Dueng-Yuan Hueng
Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC
DOI:10.4103/2152-7806.133205
Copyright: © 2014 Cheng YP This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.How to cite this article: Cheng Y, Lin C, Lin P, Cheng C, Ma H, Chen C, Hueng D. Midkine expression in high grade gliomas: Correlation of this novel marker with proliferation and survival in human gliomas. Surg Neurol Int 26-May-2014;5:78
How to cite this URL: Cheng Y, Lin C, Lin P, Cheng C, Ma H, Chen C, Hueng D. Midkine expression in high grade gliomas: Correlation of this novel marker with proliferation and survival in human gliomas. Surg Neurol Int 26-May-2014;5:78. Available from: http://sni.wpengine.com/surgicalint_articles/midkine-expression-in-high-grade-gliomas-correlation-of-this-novel-marker-with-proliferation-and-survival-in-human-gliomas/
Abstract
Background:High-grade primary glioma have poor prognosis and predictive biomarkers is very important. Midkine (MDK), a heparin-binding growth factor, is important in regulating carcinogenesis, cell proliferation, mitogenesis, and angiogenesis. This study aimed to identify over-expression of MDK in gliomas and correlate this with clinical outcomes. The authors put forward their hypothesis correlating proliferation and poor survival with over-expression of this novel protein.
Methods:Two datasets from Gene Expression Omnibus (GEO) included human data of 100 and 180 patients, respectively. The MDK expression, World Health Organization (WHO) pathological grade, sex, age, and survival time were identified for statistical analysis.
Results:A search of the GEO profile revealed that MDK expression level was statistically greater in the WHO grade IV compared with grade II (P = 0.002), in grades III and IV compared with nontumor control (P = 0.044 and P
Conclusions:Taken together, there is a positive correlation between MDK expression and WHO grading of human gliomas. Moreover, MDK over-expression is significant correlated to poor survival outcome in high-grade, suggesting that MDK may be an important therapeutic target.
Keywords: GEO profile, glioma, midkine, survival rate, WHO grades
INTRODUCTION
Gliomas are common primary brain tumors with poor outcome despite aggressive interventions.[
Midkine (MDK) is a 13-kDa heparin-binding growth factor originally found in embryonal carcinoma cells. The mechanism of MDK action plays as upstream of PI3K and MAPK signaling. MDK receptors included Notch-2, integrins, neuroglycan C, anaplastic lymphoma kinase, low-density lipoprotein receptor-related protein, and receptor protein tyrosine phosphatase Z1 (PTPζ). Thus, MDK activates the PI3K pathway and induces antiapoptotic activity. Moreover, MDK signaling affected some transcription factors, which include Hes-1, STATs, and NF-κB.[
A recent study using genomic hotspot detection has demonstrated MDK elevation in primary glioma cell lines.[
MATERIALS AND METHOD
Human MDK gene expression in GEO databases
Two GEO datasets (GDS) were enrolled. The first dataset is GDS1815. The gene array of 100 patients with primary high-grade gliomas showed 100 panels of MDK mRNA expression data in the GEO dataset for analysis [GDS1815/209035_at/MDK]. After excluding 23 panels of data missing age and survival time, 77 panels of data that displayed MDK expression, sex, age, and survival time were enrolled for statistical analysis. The second dataset is GDS1962. The gene array of 180 patients with high-grade gliomas enrolled 180 panels of MDK mRNA expression database (GDS1962/209035_at/MDK). Then, 23 cases of nontumor control, 7 grade II glioma, 19 grade III glioma, and 81 grade IV glioma with the MDK gene expression were reassessed for statistical analysis after excluding 50 panels of oligodendrocytoma data.
Statistical analysis
Categorical variables and continuous variables were presented as number (proportion) and mean ± standard deviation (SD), respectively. Differences in variables between each WHO grade of human glioma samples were compared using the Student's t-test or Chi-square test, as appropriate. The MDK expression was tested by a single tail test based on apparent trend of value in the four WHO grades. The Bonferroni method was used to adjust the P value since multi-groups test had higher possibility of type I error.
The Kaplan-Meier survival curve was used to present the relationships between MDK expression and WHO grades. The relationships were tested using the Cox proportional hazard model. The cut-off point of MDK expression was decided by statistical view as the most significant point in all cut points. Any variable that was significant in univariate analysis was controlled in the multivariate analysis. Statistical significance was set at P < 0.05. All statistical analyses were conducted using the GraphPad Prism 5 software and R 3.0.1 software.
RESULTS
MDK mRNA levels positively correlated with WHO pathological grading of human gliomas
The GEO dataset was statistically analyzed to explore the relationship between WHO pathological grading and MDK expression [
Figure 1
MDK mRNA expression in human gliomas and nontumor control. Scatter plots display the distribution of MDK gene expression in high-grade gliomas (grades III and IV) compared with low-grade glioma and nontumor controls. The WHO grading of gliomas positively correlated with increased mRNA levels of MDK. #adjusted P<0.05; $P<0.05
High MDK mRNA levels positively correlated with poor survival in human gliomas
Another GEO dataset (GDS1815/209035_at/MDK) was further analyzed to investigate the correlation among MDK expression, WHO pathologic grades, sex, age, and survival times [
In univariate analysis [
Using the Kaplan-Meier survival curve, data obtained from the GEO database (GDS1815/209035_at/MDK) was used to explore the correlation between MDK mRNA expression levels and survival of patients with grade III or grade IV gliomas [
DISCUSSION
MDK is a heparin-binding growth factor mediated cellular migration, proliferation, and survival.[
The present study reveals that the MDK gene expression is positively correlated with WHO grade and poor survival in patients with human gliomas. Similarly, Roversi recognized that MDK gene over-expression correlated with the progression of glioblastoma through genomic array profiling of 25 primary glioma cell lines.[
MDK is a plasma secreted protein identified in embryonal carcinoma cells at early stages of retinoic acid-induced differentiation.[
Nonetheless, this study has some limitations. The MDK expression positively correlates with WHO grading and survival using only a single array data (GDS1815) of human gliomas samples. Thus, the findings and conclusions may not be as robust. Alternatively, another array data (GDS1962) from different medical centers have been analyzed and this confirmed the positive correlation of MDK expression and tumor grading and survival. Importantly, MDK may also have the potential role as a proliferation marker in addition to EGFR/p53 and others that are done for GBMs,[
CONCLUSION
In conclusion, there is a positive correlation between MDK expression and WHO grading of gliomas. In high-grade gliomas, MDK over-expression appears to be significantly correlated to poor survival. Thus, MDK may be a reliable biomarker for determining clinical outcome and pathologic grading. Future studies will further clarify the role of MDK as a possible biomarker for determining clinical outcome and pathologic grading.
ACKNOWLEDGMENTS
This study was supported in part by grants from Tri-Service General Hospital, National Defense Medical Center, (TSGH-C103-005-007-009-S05), the Ministry of Health and Welfare (MOHW103-TD-B-111-12), and National Science Council (NSC 102-2628-B-016 -002 -MY2), Taipei, Taiwan, ROC.
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