Massively Parallel Signature Sequencing and Bioinformatics Analysis Identifies Up-Regulation of TGFBI and SOX4 in Human Glioblastoma

被引：74

作者：

Lin, Biaoyang ^{[1
,2
,3
]}

Madan, Anup ^{[5
]}

Yoon, Jae-Geun ^{[1
]}

Fang, Xuefeng ^{[3
]}

Yan, Xiaowei ^{[4
]}

Kim, Taek-Kyun ^{[6
,7
]}

Hwang, Daehee ^{[6
,7
]}

Hood, Leroy ^{[4
]}

Foltz, Gregory ^{[1
,4
]}

机构：

[1] Swedish Med Ctr, Swedish Neurosci Inst, Seattle, WA USA

[2] Univ Washington, Dept Urol, Seattle, WA 98195 USA

[3] Zhejiang Univ, Zhejiang Calif Int NanoSyst Inst, Hangzhou 310003, Zhejiang, Peoples R China

[4] Inst Syst Biol, Seattle, WA USA

[5] Seattle Mol Diagnost Res Inst, Bellevue, WA USA

[6] Pohang Univ Sci & Technol, Dept Chem Engn, Pohang, Kyungbuk, South Korea

[7] Pohang Univ Sci & Technol, I Bio Program, Pohang, South Korea

来源：

PLOS ONE | 2010年 / 5卷 / 04期

关键词：

GROWTH-FACTOR-BETA; GENE-EXPRESSION; MICROARRAY ANALYSIS; CELL; CANCER; PROGRESSION; TUMORIGENICITY; PROLIFERATION; TRANSCRIPTION; NEUROGRANIN;

D O I：

10.1371/journal.pone.0010210

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Background: A comprehensive network-based understanding of molecular pathways abnormally altered in glioblastoma multiforme (GBM) is essential for developing effective therapeutic approaches for this deadly disease. Methodology/Principal Findings: Applying a next generation sequencing technology, massively parallel signature sequencing (MPSS), we identified a total of 4535 genes that are differentially expressed between normal brain and GBM tissue. The expression changes of three up-regulated genes, CHI3L1, CHI3L2, and FOXM1, and two down-regulated genes, neurogranin and L1CAM, were confirmed by quantitative PCR. Pathway analysis revealed that TGF- beta pathway related genes were significantly up-regulated in GBM tumor samples. An integrative pathway analysis of the TGF beta signaling network identified two alternative TGF-beta signaling pathways mediated by SOX4 ( sex determining region Y-box 4) and TGFBI ( Transforming growth factor beta induced). Quantitative RT-PCR and immunohistochemistry staining demonstrated that SOX4 and TGFBI expression is elevated in GBM tissues compared with normal brain tissues at both the RNA and protein levels. In vitro functional studies confirmed that TGFBI and SOX4 expression is increased by TGF- beta stimulation and decreased by a specific inhibitor of TGF- beta receptor 1 kinase. Conclusions/Significance: Our MPSS database for GBM and normal brain tissues provides a useful resource for the scientific community. The identification of non-SMAD mediated TGF-beta signaling pathways acting through SOX4 and TGFBI ( GENE ID: 7045) in GBM indicates that these alternative pathways should be considered, in addition to the canonical SMAD mediated pathway, in the development of new therapeutic strategies targeting TGF-beta signaling in GBM. Finally, the construction of an extended TGF- beta signaling network with overlaid gene expression changes between GBM and normal brain extends our understanding of the biology of GBM.

引用

页数：12

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