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Malignant progression of astrocytoma is a multistep process with the integration of genetic abnormalities including grade progression and subtypes transition. Established biomarkers of astrocytomas, like IDH1 and TP53 mutation, were not associated with malignant progression.
Bioinformatics analysis revealed that EMT-associated pathways were most significantly altered along with tumor grades progress 15293 up-regulation of 17 genes.
Up-regulation of these genes was further confirmed by RNA-sequencing in samples. Survival analysis revealed that high expression of these genes indicates a poor survival outcome. The conclusion was confirmed using immunohistochemistry in tissue microarrays. Astrocytomas are the most prevalent primary brain tumor and characterized by invasive and rapid growth.
Tumor cells achieve rapid invasion and long-distance migration from the tumor mass into the normal brain tissue, and these processes are responsible for tumor recurrence. The invasion of tumor cells increases gradually with tumor grade progress. At present, histomorphology remains the only criterion for the diagnosis of astrocytomas. According to the world health organization WHO standards, the grading is based on the presence or absence of nuclear atypia, mitosis, vascular proliferation, and necrosis [ 1 ].
Low grade astrocytomas with characteristic of nuclear atypia or mitosis have longer survival but ultimately transform to a higher grade tumor with increasing malignancy vascular proliferation or necrosis. However, there also exists different malignant degree on the equal grade that corresponds to different prognosis [ 23 ]. Therefore, the malignant phenotype of astrocytomas cannot be well characterized by the current grading system.
Advances in molecular genetics are challenging the traditional morphological categorization of tumors. The theory that glioma is a result of polygenic disorder is increasingly being recognized.
Gene expression abnormalities are associated with progression of gliomas and can differentiate not only among histologic subtypes but also between low and high grade gliomas [ 45 ]. Molecular alterations on primary GBM arising de novo have been studied thoroughly. Recently, Jiao et al. These classical alterations were generally considered as the earliest genetic abnormalities in the development of astrocytomas.
But the high frequency of these alterations are already present in low grade gliomas AII and the frequency does not increase even decrease in high grade gliomas AIII or GBM suggesting that they might not associated with malignant progression of astrocytomas.
More importantly, there also exists another malignant progression on the equal grade of tumors subtypes transition.
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Different subtypes have different malignant phenotypes that were also resulted from many genetic alterations [ 310 ]. Therefore, discovery of new driver markers would help to understand molecular mechanisms of astrocytomas progression. The aim of the present study was to identify genetic alterations involved in the malignant progression of astrocytomas. Secondary GBM not to be included in the study due to patients undergo a second operation or chemoradiotherapy that might affect gene expression [ 11 ].
The established biomarkers of astrocytomas, like IDH1 and TP53 mutation, were not associated with malignant progression though could predict survival in the present or previous studies [ 12 ]. In addition, TGFB1I1 might be associated with subtype transition and could be used as serviceable marker for mensenchymal astrocytoma.
This finding is new opportunity for understanding the fundamental basis for malignant progression of astrocytomas and also provide novel interfering target for shutting down astrocytomas progression. At present, many reliable molecular markers, such as TP53 and IDH1 mutation, have been accepted as early alterations in astrocytomas development [ 67 ]. In this study, we asked whether these master markers are changed with increasing tumor grades.
To avoid discrepancies due to different platforms, the data were analyzed separately within each database. After overlapping the analyzed data, a total of up-regulated genes and down-regulated genes were identified in AII compared with NBT step1. B A hematoxylin and eosin stained section was performed to determine the pathological type and grade and dysregulated genes were divided into up-regulated and down-regulated during malignant progression of astrocytomas.
To further understand the changes in differentially genes and pathways of astrocytomas, Gene-set enrichment analysis were performed using a comprehensive set of functional annotation tool The Database for Annotation, Visualization and Integrated Discovery, DAVID [ 13 ]. Overall, these differential pathways might contribute to an understanding of the molecular determinants that drive grade progress of astrocytomas.
This finding indicates that these candidate genes might also contribute to the subtype transition. A Transcripts levels of 29 candidate genes were identified in three databases and significantly increased with increasing grades data on the other two databases are supplied in supplementary table 2 ; TCGA subtypes were given in different colors.
Survival analysis was performed by Kaplan-meier plot on candidate genes: B up-regulated genes; C down-regulated genes. However, except for KPS, cox repression analysis showed that there were no significant correlation between patient survival and age, sex, TP53 mutation and even IDH1 mutation and 1p19q loss Supplementary Table 3.
The fact that high expression of TGFB1I1 indicated a poor survival outcome suggests that TGFB1I1 might play important role in malignant progression of astrocytomas by driving cell invasion and migration. We found that gene pathway terms were enriched for cell adhesion and ECM-receptor interaction that was consistent with the above pathway analysis.
Among the 10 mice transplanted with parental U87 cells, 6 mice were found tumors in brains. Malignant astrocytomas exhibit a relentless malignant progression characterized by widespread invasion throughout the brain. Most patients with low grade gliomas progress to high grade gliomas with increasing malignant degree. However, there also exists malignant progression in equal grade tumors that has been little 125993. The subtypes on the equal grade tumors, like mesenchymal and proneural subtype on GBM, can transit each other [ 20 ].
Understanding the mechanism of grade progression and subtypes transition and blocking the main oncogenic pathway are the crux of gliomas therapy.
Increasing evidences showed that genetic alterations mutation, deletion, amplification and overexpression were involved in the genesis and progression of gliomas [ 21 ].
Established biomarkers of astrocytomas, such as TP53 and IDH1 mutation, and even recently discovered TERT promoter mutations, were considered to be the early event of astrocytomas. Moreover, patients with IDH1 mutation frequently leii TP53 mutation, indicating that this alteration was an earlier event in astrocytomas development than TP53 mutation.
Bioinformatics analysis of the RNA expression data followed by pathway analysis revealed that the EMT-associated pathways were most significantly altered along increasing tumor grades with up-regulation of 17 genes. All of the 17 candidate genes were significantly up-regulated with increasing tumor grade and associated with malignant phenotype in various tumors. TGFB1I1 has also been shown to function as an oncogene by inducing EMT to promote invasion in cancer cells as well as in normal breast epithelial cells [ 24 ].
Survival analysis showed high expression of these candidate genes indicates poor outcome of patients with astrocytomas. This comprehensive demonstration of these gene changes pei serve as a model for studies to understand the complex mechanisms of astrocytomas progression.
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The activation of EMT program has been proposed as the critical mechanism for the acquisition of malignant phenotypes. Studies in vivo and in vitro have demonstrated that EMT contributes to tumor progression and subtypes transition [ 25 ].
Moreover, we found that high expression of TGFB1I1 might contribute to the malignant transition from endothelial-like phenotype to mesenchymal-like phenotype.
Finally, these results were further confirmed in vivo experiments. In conclusion, this finding oei new opportunity for understanding the fundamental basis for malignant progression of astrocytomas and the candidate genes might be novel interfering targets for astrocytomas therapy.
The mean age of diagnosis is Patients with AIII have a slightly later median age of onset of about Males are slightly more commonly affected, with a male to female ratio of about 1. These samples were used to perform mRNA expression profiles, RNA-sequencing, detection of the established biomarkers, immunohistochemistry and survival analysis. The numbers of sample in each ldi were mentioned in following sections. Normal adult brain samples were obtained after informed consent from patients with severe traumatic brain injury who needed 122593 surgery and from patients who had undergone surgery for primary epilepsy.
All of the patients underwent surgical resection from January through December Patients were eligible for the study if their diagnosis was established histologically by 2 neuropathologists according to the WHO classification guidelines. This study was approved by the institutional review boards of all hospitals involved in the study, and written informed consent was obtained from all patients. Stably transfected cells were selected for with 0.
PCR included the following components: Each cDNA sample was run as triplicates. Immunohistochemistry IHC of paraffin sections in tissue microarrays and immunocytofluorescent 12539 in H4 cell line were performed as previously described [ 29 ]. After washing with Tris-buffer, the sections were stained with DAB for le min, rinsed in water and counterstained with hematoxylin.
IF was performed on H4 cell line. Briefly, cells were incubated with primary antibody for 1 h at room temperature. FITC-labeled secondary antibodies were added at 1: Whole-cell lysates were prepared using RIPA buffer. Following 24 h incubation, the non-invading cells were removed from the upper surfaces of the invasion membranes and the cells on the lower surface were stained with crystal violet.
The average number of cells per field was determined by counting cells in 6 random fields per well. Cells were grown in 6-well plates with complete medium.
The wounds were observed under a phase contrast microscope IX81, Olympus. The images were analysed by drawing lines at the wound edges. The width of the scratch was measured at 0, 8, 18 and 24 h post-treatment. Mice were sacrificed after 25 days simultaneously. Differentially expression genes were detected by unpaired Student’s t-test. Kaplan-Meier survival analysis was used to estimate the survival distributions.
The log-rank test was applied to assess the statistical significance between stratified survival groups using the GraphPad Prism version 4. Heat maps of different grade astrocytomas were constructed by Gene Cluster 3. This work was supported by grants from Beijing science and technology plan No. Disclose any potential conflicts of interest. National Center for Biotechnology InformationU. Lfi List Oncotarget v. Published online Dec Author information Article notes Copyright and License information Disclaimer.
Received Apr 28; Accepted Sep 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.