title: 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-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.
authors.affiliation: Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. Chinese Glioma Cooperative Group (CGCG), China.
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. Chinese Glioma Cooperative Group (CGCG), China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, China.
authors.forename: Kuanyu
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. Chinese Glioma Cooperative Group (CGCG), China.
authors.forename: Chuanbao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. Chinese Glioma Cooperative Group (CGCG), China.
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Molecular Neuropathology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China. Chinese Glioma Cooperative Group (CGCG), China.
authors.forename: Kun
authors.initials: K
authors.lastname: Yao
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. Chinese Glioma Cooperative Group (CGCG), China.
authors.forename: Pei
authors.initials: P
authors.lastname: Yang
authors.affiliation: Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin Medical University, Tianjin, China. Chinese Glioma Cooperative Group (CGCG), China.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin Medical University, Tianjin, China. Chinese Glioma Cooperative Group (CGCG), China.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Kang
authors.affiliation: Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. Chinese Glioma Cooperative Group (CGCG), China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. Chinese Glioma Cooperative Group (CGCG), China. China National Clinical Research Center for Neurological Diseases, China. Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D060588:LIM Domain Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D011379:Prognosis
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C490351:TGFB1I1 protein, human