Landscape of MicroRNA Regulatory Network Architecture and Functional Rerouting in Cancer.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
04 01 2023
04 01 2023
Historique:
received:
03
02
2020
revised:
15
12
2020
accepted:
14
10
2022
pubmed:
21
10
2022
medline:
6
1
2023
entrez:
20
10
2022
Statut:
ppublish
Résumé
Somatic mutations are a major source of cancer development, and many driver mutations have been identified in protein coding regions. However, the function of mutations located in miRNA and their target binding sites throughout the human genome remains largely unknown. Here, we built detailed cancer-specific miRNA regulatory networks across 30 cancer types to systematically analyze the effect of mutations in miRNAs and their target sites in 3' untranslated region (3' UTR), coding sequence (CDS), and 5' UTR regions. A total of 3,518,261 mutations from 9,819 samples were mapped to miRNA-gene interactions (mGI). Mutations in miRNAs showed a mutually exclusive pattern with mutations in their target genes in almost all cancer types. A linear regression method identified 148 candidate driver mutations that can significantly perturb miRNA regulatory networks. Driver mutations in 3'UTRs played their roles by altering RNA binding energy and the expression of target genes. Finally, mutated driver gene targets in 3' UTRs were significantly downregulated in cancer and functioned as tumor suppressors during cancer progression, suggesting potential miRNA candidates with significant clinical implications. A user-friendly, open-access web portal (mGI-map) was developed to facilitate further use of this data resource. Together, these results will facilitate novel noncoding biomarker identification and therapeutic drug design targeting the miRNA regulatory networks. A detailed miRNA-gene interaction map reveals extensive miRNA-mediated gene regulatory networks with mutation-induced perturbations across multiple cancers, serving as a resource for noncoding biomarker discovery and drug development.
Identifiants
pubmed: 36265133
pii: 711846
doi: 10.1158/0008-5472.CAN-20-0371
pmc: PMC9811166
mid: NIHMS1845460
doi:
Substances chimiques
MicroRNAs
0
3' Untranslated Regions
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
59-73Subventions
Organisme : NCI NIH HHS
ID : U01 CA217842
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM137836
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM133658
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA240689
Pays : United States
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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