miR-27a is a master regulator of metabolic reprogramming and chemoresistance in colorectal cancer.
AMP-Activated Protein Kinase Kinases
Adult
Aged
Aged, 80 and over
Cell Proliferation
/ drug effects
Cellular Reprogramming
/ drug effects
Cisplatin
/ pharmacology
Colorectal Neoplasms
/ drug therapy
Drug Resistance, Neoplasm
/ drug effects
Female
Gene Expression Regulation, Neoplastic
/ drug effects
HCT116 Cells
Humans
Male
MicroRNAs
/ genetics
Middle Aged
Protein Kinases
/ genetics
Signal Transduction
/ drug effects
TOR Serine-Threonine Kinases
/ genetics
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
25
10
2019
accepted:
12
02
2020
revised:
27
01
2020
pubmed:
7
3
2020
medline:
23
12
2020
entrez:
6
3
2020
Statut:
ppublish
Résumé
Metabolic reprogramming towards aerobic glycolysis in cancer supports unrestricted cell proliferation, survival and chemoresistance. The molecular bases of these processes are still undefined. Recent reports suggest crucial roles for microRNAs. Here, we provide new evidence of the implication of miR-27a in modulating colorectal cancer (CRC) metabolism and chemoresistance. A survey of miR-27a expression profile in TCGA-COAD dataset revealed that miR-27a-overexpressing CRCs are enriched in gene signatures of mitochondrial dysfunction, deregulated oxidative phosphorylation, mTOR activation and reduced chemosensitivity. The same pathways were analysed in cell lines in which we modified miR-27a levels. The response to chemotherapy was investigated in an independent cohort and cell lines. miR-27a upregulation in vitro associated with impaired oxidative phosphorylation, overall mitochondrial activities and slight influence on glycolysis. miR-27a hampered AMPK, enhanced mTOR signalling and acted in concert with oncogenes and tumour cell metabolic regulators to force an aerobic glycolytic metabolism supporting biomass production, unrestricted growth and chemoresistance. This latter association was confirmed in our cohort of patients and cell lines. We disclose an unprecedented role for miR-27a as a master regulator of cancer metabolism reprogramming that impinges on CRC response to chemotherapy, underscoring its theragnostic properties.
Sections du résumé
BACKGROUND
Metabolic reprogramming towards aerobic glycolysis in cancer supports unrestricted cell proliferation, survival and chemoresistance. The molecular bases of these processes are still undefined. Recent reports suggest crucial roles for microRNAs. Here, we provide new evidence of the implication of miR-27a in modulating colorectal cancer (CRC) metabolism and chemoresistance.
METHODS
A survey of miR-27a expression profile in TCGA-COAD dataset revealed that miR-27a-overexpressing CRCs are enriched in gene signatures of mitochondrial dysfunction, deregulated oxidative phosphorylation, mTOR activation and reduced chemosensitivity. The same pathways were analysed in cell lines in which we modified miR-27a levels. The response to chemotherapy was investigated in an independent cohort and cell lines.
RESULTS
miR-27a upregulation in vitro associated with impaired oxidative phosphorylation, overall mitochondrial activities and slight influence on glycolysis. miR-27a hampered AMPK, enhanced mTOR signalling and acted in concert with oncogenes and tumour cell metabolic regulators to force an aerobic glycolytic metabolism supporting biomass production, unrestricted growth and chemoresistance. This latter association was confirmed in our cohort of patients and cell lines.
CONCLUSIONS
We disclose an unprecedented role for miR-27a as a master regulator of cancer metabolism reprogramming that impinges on CRC response to chemotherapy, underscoring its theragnostic properties.
Identifiants
pubmed: 32132656
doi: 10.1038/s41416-020-0773-2
pii: 10.1038/s41416-020-0773-2
pmc: PMC7188668
doi:
Substances chimiques
MIRN27 microRNA, human
0
MicroRNAs
0
Protein Kinases
EC 2.7.-
MTOR protein, human
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
AMP-Activated Protein Kinase Kinases
EC 2.7.11.3
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1354-1366Commentaires et corrections
Type : ErratumIn
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