Multidimensional analysis of gene expression reveals TGFB1I1-induced EMT contributes to malignant progression of astrocytomas.
Multidimensional analysis of gene expression reveals TGFB1I1-induced EMT contributes to malignant progression of astrocytomas.
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基因表达的多维分析表明 TGFB1I1 诱导的 EMT 有助于星形细胞瘤的恶性进展。
DOI：
10.18632/oncotarget.2518
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发表时间：
2014-12-30
期刊：
影响因子：
--
通讯作者：
Jiang T
中科院分区：
文献类型：
--
作者：
Liu Y;Hu H;Wang K;Zhang C;Wang Y;Yao K;Yang P;Han L;Kang C;Zhang W;Jiang T
星形细胞瘤的恶性进展是一个多步骤的过程，包括分级进展和亚型转换，其中整合了遗传异常。星形细胞瘤的既定生物标志物，如IDH 1和TP 53突变，与恶性进展无关。为了鉴定有助于恶性进展的新生物标志物，我们收集了252个具有全基因组mRNA表达谱的样本[34个正常脑组织（NBT），136个II级星形细胞瘤（AII）和82个III级星形细胞瘤（AIII）]。生物信息学分析显示，EMT相关通路随着肿瘤分级的进展沿着发生最显著的改变，其中17个基因表达上调。通过128个样品中的RNA测序进一步证实了这些基因的上调。生存分析表明，这些基因的高表达表明生存结果差。我们重点研究TGF-β1诱导转录本1（TGF-β1 induced transcript 1，TGF-β1 I1），并通过qPCR在6种不同级别的细胞系和49例独立样本（36例AIIs和13例AIIs）中进一步验证了TGF-β 1 I1表达与WHO分级的相关性。TGFB 1 I1的高表达与亚型转换和EMT通路的激活有关。该结论在组织微阵列中使用免疫组织化学得到证实。使用TGF-β1和TGFB 1 I1 shRNA的体外和体内研究表明，TGFB 1 I1是TGF-β刺激的EMT所必需的，EMT有助于星形细胞瘤的恶性进展。
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. To identify new biomarker(s) contributing to malignant progression, we collected 252 samples with whole genome mRNA expression profile [34 normal brain tissue (NBT), 136 grade II astrocytoma (AII) and 82 grade III astrocytoma (AIII)]. Bioinformatics analysis revealed that EMT-associated pathways were most significantly altered along with tumor grades progress with up-regulation of 17 genes. Up-regulation of these genes was further confirmed by RNA-sequencing in 128 samples. Survival analysis revealed that high expression of these genes indicates a poor survival outcome. We focused on TGFB1I1 (TGF-β1 induced transcript 1) whose expression correlation with WHO grades was further validated by qPCR in 6 cell lines of different grades and 49 independent samples (36 AIIs and 13 AIIIs). High expression of TGFB1I1 was found associated with subtype transition and EMT pathways activation. The conclusion was confirmed using immunohistochemistry in tissue microarrays. Studies in vitro and in vivo using TGF-β1 and TGFB1I1 shRNA demonstrated that TGFB1I1 is required for TGF-β stimulated EMT that contributes to malignant progression of astrocytomas.
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