Dataset Information

NOTCH2/NOTCH3/DLL3/MAML1/ADAM17 signaling network is associated with ovarian cancer.

ABSTRACT: Notch signaling is well-known for its role in regulating cell self-renewal and differentiation. Within the cancer research field, it has been identified that dysregulated Notch signaling is involved directly with various types of cancer. Although Notch signaling is generally considered as oncogenic, it sometimes acts as a tumor suppressor, highlighting the complexity of the role of Notch in cancer. A number of studies have associated Notch signaling components with ovarian cancer, but the underlying molecular mechanisms are not well-elucidated. In the present study, the roles of main components of Notch signaling in ovarian cancer were systematically analyzed through large data portals, including Prediction of Clinical Outcomes from Genomic Profiles, Gene Expression across Normal and Tumor tissue, CSIOVDB, Broad Institute Cancer Cell Line Encyclopedia and cBioPortal. Upregulated expression of proteins in the Notch signaling pathway components in ovarian cancer was identified to be generally associated with poor overall and disease-free survival time, and more advanced cancer stages. In addition, Notch components were enriched in ovarian cancer tissues and cell lines. These results led to a proposed neurogenic locus notch homolog protein (NOTCH)2/NOTCH3/Delta-like protein 3/Mastermind-like protein 1/a disintegrin and metalloproteinase domain-containing protein 17 network. Anticancer drugs, developed to target this network, may have high specificity in treating Notch-associated ovarian cancer.

SUBMITTER: Jia D

PROVIDER: S-EPMC6507302 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

NOTCH2/NOTCH3/DLL3/MAML1/ADAM17 signaling network is associated with ovarian cancer.

Jia Dongyu D Underwood Jesse J Xu Qiuping Q Xie Qian Q

Oncology letters 20190319 6

Notch signaling is well-known for its role in regulating cell self-renewal and differentiation. Within the cancer research field, it has been identified that dysregulated Notch signaling is involved directly with various types of cancer. Although Notch signaling is generally considered as oncogenic, it sometimes acts as a tumor suppressor, highlighting the complexity of the role of Notch in cancer. A number of studies have associated Notch signaling components with ovarian cancer, but the underl ...[more]

PMID: 31186700

Similar Datasets

Project description:The Notch3 signaling pathway is thought to play a critical role in cancer development, as evidenced by the Notch3 amplification and rearrangement observed in human cancers. However, the molecular mechanism by which Notch3 signaling contributes to tumorigenesis is largely unknown. In an effort to identify the molecular modulators of the Notch3 signaling pathway, we screened for Notch3-intracellular domain (N3-ICD) interacting proteins using a human proteome microarray. Pathway analysis of the Notch3 interactome demonstrated that ubiquitin C was the molecular hub of the top functional network, suggesting the involvement of ubiquitination in modulating Notch3 signaling. Thereby, we focused on functional characterization of an E3 ubiquitin-protein ligase, WWP2, a top candidate in the Notch3 interactome list. Co-immunoprecipitation experiments showed that WWP2 interacted with N3-ICD but not with intracellular domains from other Notch receptors. Wild-type WWP2 but not ligase-deficient mutant WWP2 increases mono-ubiquitination of the membrane-tethered Notch3 fragment, therefore attenuating Notch3 pathway activity in cancer cells and leading to cell cycle arrest. The mono-ubiquitination by WWP2 may target an endosomal/lysosomal degradation fate for Notch3 as suggested by the fact that the process could be suppressed by the endosomal/lysosomal inhibitor. Analysis of The Cancer Genome Atlas dataset showed that the majority of ovarian carcinomas harbored homozygous or heterozygous deletions in WWP2 locus, and there was an inverse correlation in the expression levels between WWP2 and Notch3 in ovarian carcinomas. Furthermore, ectopic expression of WWP2 decreased tumor development in a mouse xenograft model and suppressed the Notch3-induced phenotypes including increase in cancer stem cell-like cell population and platinum resistance. Taken together, our results provide evidence that WWP2 serves as a tumor suppressor by negatively regulating Notch3 signaling in ovarian cancer.

Dataset Information

NOTCH2/NOTCH3/DLL3/MAML1/ADAM17 signaling network is associated with ovarian cancer.

Publications

NOTCH2/NOTCH3/DLL3/MAML1/ADAM17 signaling network is associated with ovarian cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets