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Impact of MACC1 on human malignant glioma progression and patients' unfavorable prognosis.

ABSTRACT: BACKGROUND: Metastasis-associated in colon cancer 1 (MACC1) has been established as an independent prognostic indicator of metastasis formation and metastasis-free survival for patients with colon cancer and other solid tumors. However, no data are available concerning MACC1 expression in human astrocytic tumors. Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor of adulthood, and due to its invasive and rapid growth, patients have unfavorable prognoses. Although these tumors rarely metastasize, their invasive and migratory behavior is similar to those of metastatic cells of tumors of different origin. Thus, we hypothesized that MACC1 may be involved in progression of human gliomas. METHODS: We performed real-time measurements of proliferation and migration in MACC1-transfected GBM cell lines (U138, U251) and evaluated tumor formation in organotypic hippocampal slice cultures of mice. Semiquantitative and quantitative real-time reverse transcription PCR analyses were performed for MACC1 and for its transcriptional target c-Met in human astrocytoma of World Health Organization grade II (low-grade astrocytoma) and GBM biopsies. Data were validated by MACC1 immunohistochemistry in independent matched samples of low-grade astrocytoma and GBM. RESULTS: MACC1 increases the proliferative, migratory, and tumor-formation abilities of GBM cells. The c-Met inhibitor crizotinib reduced MACC1-induced migration and tumor formation in organotypic hippocampal slice cultures of mice. Analyzing patients' biopsies, MACC1 expression increased concomitantly with increasing World Health Organization grade. Moreover, MACC1 expression levels allowed discrimination of dormant and recurrent low-grade astrocytomas and of primary and secondary GBM. Strong MACC1 expression correlated with reduced patient survival. CONCLUSIONS: MACC1 may represent a promising biomarker for prognostication and a new target for treatment of human gliomas.

SUBMITTER: Hagemann C

PROVIDER: S-EPMC3829600 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Impact of MACC1 on human malignant glioma progression and patients' unfavorable prognosis.

Hagemann Carsten C Fuchs Steffen S Monoranu Camelia M CM Herrmann Pia P Smith Janice J Hohmann Tim T Grabiec Urszula U Kessler Almuth F AF Dehghani Faramarz F Löhr Mario M Ernestus Ralf-Ingo RI Vince Giles H GH Stein Ulrike U

Neuro-oncology 20131111 12

<h4>Background</h4>Metastasis-associated in colon cancer 1 (MACC1) has been established as an independent prognostic indicator of metastasis formation and metastasis-free survival for patients with colon cancer and other solid tumors. However, no data are available concerning MACC1 expression in human astrocytic tumors. Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor of adulthood, and due to its invasive and rapid growth, patients have unfavorable prognoses. Although thes ...[more]

PMID: 24220141

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Project description:BackgroundGlioblastoma multiforme (GBM) is the most common type of glioma, and the most aggressive brain malignancy in adults. This study sought to identify novel survival-status related markers, and examine their function in glioma.MethodsThe gene expression, survival heatmaps, and Kaplan-Meier survival plots of the genes were analyzed by using gene expression profiling interactive analysis (GEPIA) dataset, Linked Omics. The single-cell data analysis and tumor immune infiltration analysis was conducted by Tumor Immune Estimation Resource (TIMER) dataset. DBTRG and U251 cells with silenced Deltex E3 ubiquitin ligase 2 (DTX2) expression were constructed and used for Cell Counting Kit 8 (CCK-8), and wound healing assay in vitro. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis was used to explore the histone activation marks and transcription factors DTX2 promoter. Dual-luciferase assays were carried out to detect the luciferase activities of bromodomain containing 4 (BRD4) binding to DTX2.ResultsWe first conducted a survival-status analysis to identify survival status-related genes in The Cancer Genome Atlas GBM and low-grade glioma data sets. A subsequent analysis identified 3 novel prognostic biomarkers; that is, DTX2, cytochrome P450 oxidoreductase, and Williams-Beuren syndrome chromosomal region 16 protein. In the validation Chinese Glioma Genome Atlas data sets, DTX2 showed the best performance, and was examined in a further analysis. Next, 3 short-hairpin ribonucleic acids were designed to silence DTX2 expression, and CCK-8 and wound-healing assays were applied to study the function of DTX2. We found that DTX2-silenced glioma cells exhibited a significant decrease in their growth and migration capabilities. Finally, the molecular basis for increased DTX2 in glioma was investigated via ChIP-Seq analysis and luciferase assays. The analysis revealed that DTX2 was transcriptionally activated by BRD4.ConclusionsIn conclusion, BRD4 transcriptionally activates DTX2, contributes to glioma progression, predicts an unfavorable prognosis, and could provide new options for glioma prognosis prediction and treatment.

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Impact of MACC1 on human malignant glioma progression and patients' unfavorable prognosis.

Publications

Impact of MACC1 on human malignant glioma progression and patients' unfavorable prognosis.

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