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Multidimensional analysis of gene expression reveals TGFB1I1-induced EMT contributes to malignant progression of astrocytomas.

ABSTRACT: 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-?1 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-?1 and TGFB1I1 shRNA demonstrated that TGFB1I1 is required for TGF-? stimulated EMT that contributes to malignant progression of astrocytomas.

SUBMITTER: Liu Y

PROVIDER: S-EPMC4350345 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Multidimensional analysis of gene expression reveals TGFB1I1-induced EMT contributes to malignant progression of astrocytomas.

Liu Yanwei Y Hu Huimin H Wang Kuanyu K Zhang Chuanbao C Wang Yinyan Y Yao Kun K Yang Pei P Han Lei L Kang Chunsheng C Zhang Wei W Jiang Tao T

Oncotarget 20141201 24

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 astrocytom ...[more]

PMID: 25333259

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Project description:Aberrant methylation is one of the most frequent epigenetic alterations that regulate the expression levels of genes, including long non‑coding RNAs (lncRNAs), in tumors. However, to the best of our knowledge, the expression and function of hepatic nuclear factor 1α antisense RNA 1 (HNF1A‑AS1) and its methylation condition have not yet been reported in the development and progression of laryngeal squamous cell carcinoma (LSCC). In the present study, the expression and methylation of HNF1A‑AS1 were first examined by reverse transcription‑quantitative PCR, bisulfite genomic sequencing and methylation‑specific polymerase chain reaction in samples from patients with LSCC, which were based on the in silico analysis using The Cancer Genome Atlas data, and were then further verified in LSCC cell lines with and without 5‑Aza‑2'‑deoxycytidine (5‑Aza‑dC) treatment. Subsequently, proliferation, cell cycle distribution, migration and invasion of LSCC cells following either knockdown or overexpression of HNF1A‑AS1 were determined in vitro. Furthermore, the characteristic of HNF1A‑AS1 on epithelial‑mesenchymal transition (EMT) changes was investigated in vitro and in vivo. The associations between the expression levels of HNF1A‑AS1 and tumorigenicity and cervical lymph node metastasis were assessed in a xenograft model in nude mice. In the present study, downregulation and hypermethylation in CpG sites of HNF1A‑AS1 were detected in LSCC tissues as well as metastatic cervical lymph nodes samples when compared with those in the adjacent non‑tumor tissues. Additionally, HNF1A‑AS1 inhibited proliferation, migration and invasion of LSCC cells in vitro by regulating the process of EMT. Furthermore, HNF1A‑AS1 inhibited tumor growth and metastasis by regulating EMT in vivo. Additionally, the migration and invasion abilities, and the expression levels of HNF1A‑AS1 and EMT markers in LSCC cells were significantly reversed by treatment with 5‑Aza‑dC. In summary, HNF1A‑AS1 was downregulated by hypermethylation in LSCC and laryngeal cancer cells. These findings suggested that HNF1A‑AS1 could serve as a tumor suppressor lncRNA in LSCC by regulating the EMT process, leading to the discovery of novel therapeutic targets and strategies for the treatment of patients with LSCC.

Dataset Information

Multidimensional analysis of gene expression reveals TGFB1I1-induced EMT contributes to malignant progression of astrocytomas.

Publications

Multidimensional analysis of gene expression reveals TGFB1I1-induced EMT contributes to malignant progression of astrocytomas.

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