Multiscale network analysis reveals molecular mechanisms and key regulators of the tumor microenvironment in gastric cancer.
Adult
Aged
Aged, 80 and over
Carrier Proteins
/ genetics
Cell Line, Tumor
Cell Proliferation
/ genetics
Cohort Studies
Computational Biology
Datasets as Topic
Disease-Free Survival
Epigenesis, Genetic
Female
Gastrectomy
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Humans
Kaplan-Meier Estimate
Male
Middle Aged
Neoplasm Invasiveness
/ genetics
Prognosis
Stomach
/ pathology
Stomach Neoplasms
/ genetics
Tumor Microenvironment
/ genetics
Young Adult
DNA methylation
gastric cancer
gene coexpression network
key driver
network module
somatic mutations
tumor microenvironment
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
01 03 2020
01 03 2020
Historique:
received:
02
04
2019
revised:
18
07
2019
accepted:
16
08
2019
pubmed:
30
8
2019
medline:
15
2
2020
entrez:
30
8
2019
Statut:
ppublish
Résumé
Gastric cancer (GC) is the third leading cause of cancer deaths and the fourth most prevalent malignancy worldwide. The high incidence and mortality rates of gastric cancer result from multiple factors such as ineffective screening, diagnosis, and limited treatment options. In our study, we sought to systematically identify predictive molecular networks and key regulators to elucidate complex interacting signaling pathways in GC. We performed an integrative network analysis of the transcriptomic data in The Cancer Genome Atlas (TCGA) gastric cancer cohort and then comprehensively characterized the predictive subnetworks and key regulators by the matched genetic and epigenetic data. We identified 221 gene subnetworks (modules) in GC. The most prognostic subnetworks captured multiple aspects of the tumor microenvironment in GC involving interactions among stromal, epithelial and immune cells. We revealed the genetic and epigenetic underpinnings of those subnetworks and their key transcriptional regulators. We computationally predicted and experimentally validated specific mechanisms of anticancer effects of GKN2 in gastric cancer proliferation and invasion in vitro. The network models and the key regulators of the tumor microenvironment in GC identified here pave a way for developing novel therapeutic strategies for GC.
Identifiants
pubmed: 31463974
doi: 10.1002/ijc.32643
pmc: PMC7004118
doi:
Substances chimiques
Carrier Proteins
0
GKN2 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1268-1280Subventions
Organisme : NIH HHS
ID : S10 OD018522
Pays : United States
Organisme : NIH HHS
ID : S10 OD026880
Pays : United States
Informations de copyright
© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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