Dynamic bioenergetic alterations in colorectal adenomatous polyps and adenocarcinomas.
Adenocarcinoma
/ diagnostic imaging
Adenomatous Polyps
/ diagnostic imaging
Aged
Aged, 80 and over
Biomarkers
Cell Line, Tumor
Colorectal Neoplasms
/ diagnostic imaging
DNA, Mitochondrial
Energy Metabolism
Female
Fluorodeoxyglucose F18
Humans
Intestinal Mucosa
Male
Middle Aged
Mitochondria
/ genetics
Monocarboxylic Acid Transporters
/ genetics
Muscle Proteins
/ genetics
Mutation
Neoplasm Staging
Oxidative Phosphorylation
Oxygen Consumption
Positron Emission Tomography Computed Tomography
Tumor Burden
Bioenergetics
Colorectal adenomatous polyp
Colorectal cancer
Glycolysis
Mitochondrial oxidative phosphorylation
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Jun 2019
Jun 2019
Historique:
received:
13
06
2018
revised:
11
05
2019
accepted:
13
05
2019
pubmed:
28
5
2019
medline:
18
12
2019
entrez:
25
5
2019
Statut:
ppublish
Résumé
Energy metabolism in carcinogenesis is poorly understood. It is widely accepted the majority of colorectal cancers (CRCs) arise from adenomatous polyps (APs). We aimed to characterize the bioenergetic alterations in APs and CRCs. Fifty-six APs, 93 CRCs and adjacent normal mucosae were tested. Oxygen consumption rate (OCR) was measured representing mitochondrial oxidative phosphorylation (OxPhos), and extracellular acidification rate (ECAR)was measured representing glycolysis. Mitochondrial DNA (mtDNA) variants and mutations were studied. Over-expressed metabolic genes in APs were identified by microarray and validated by qRT-PCR, Western blots and immunohistochemistry. Identified genes were knocked down in WiDr and colo205 CRC cell lines, and their expression was analyzed in APs/CRCs with enhanced glycolysis. ECAR, not OCR, was significantly increased in APs. While no difference of ECAR was found between CRCs and normal mucosae, OCR was significantly reduced in CRCs. OCR/ECAR ratio was decreased in APs over 1 cm, APs with a villous component and CRCs, indicating their glycolytic tendencies. The number of mtDNA mutations was increased in APs and CRCs, but not correlated with metabolic profiles. Two metabolic genes ALDOB and SLC16A4 were up-regulated in APs. Both ALDOB-knockdown and SLC16A4-knockdown CRC cell lines showed increased basal motichondrial OxPhos and decreased basal glycolysis. Moreover, the increase of mitochondrial ATP-linked respiration and the decrease of glycolytic capacity were showed in SLC16A4-knockdown cells. Finally, APs/CRCs with enhanced glycolysis had increased SLC16A4 expression. ATP production shifts from OxPhos to glycolysis in the process of AP enlargement and villous transformation. OxPhos defects are present in CRCs but not in APs. APs and CRCs tend to accumulate mtDNA mutations, but these are not correlated with bioenergetic profiles. Finally, the ALDOB and SLC16A4 may contribute to the glycolytic shift in APs/CRCs.
Sections du résumé
BACKGROUND
BACKGROUND
Energy metabolism in carcinogenesis is poorly understood. It is widely accepted the majority of colorectal cancers (CRCs) arise from adenomatous polyps (APs). We aimed to characterize the bioenergetic alterations in APs and CRCs.
METHODS
METHODS
Fifty-six APs, 93 CRCs and adjacent normal mucosae were tested. Oxygen consumption rate (OCR) was measured representing mitochondrial oxidative phosphorylation (OxPhos), and extracellular acidification rate (ECAR)was measured representing glycolysis. Mitochondrial DNA (mtDNA) variants and mutations were studied. Over-expressed metabolic genes in APs were identified by microarray and validated by qRT-PCR, Western blots and immunohistochemistry. Identified genes were knocked down in WiDr and colo205 CRC cell lines, and their expression was analyzed in APs/CRCs with enhanced glycolysis.
FINDINGS
RESULTS
ECAR, not OCR, was significantly increased in APs. While no difference of ECAR was found between CRCs and normal mucosae, OCR was significantly reduced in CRCs. OCR/ECAR ratio was decreased in APs over 1 cm, APs with a villous component and CRCs, indicating their glycolytic tendencies. The number of mtDNA mutations was increased in APs and CRCs, but not correlated with metabolic profiles. Two metabolic genes ALDOB and SLC16A4 were up-regulated in APs. Both ALDOB-knockdown and SLC16A4-knockdown CRC cell lines showed increased basal motichondrial OxPhos and decreased basal glycolysis. Moreover, the increase of mitochondrial ATP-linked respiration and the decrease of glycolytic capacity were showed in SLC16A4-knockdown cells. Finally, APs/CRCs with enhanced glycolysis had increased SLC16A4 expression.
INTERPRETATION
CONCLUSIONS
ATP production shifts from OxPhos to glycolysis in the process of AP enlargement and villous transformation. OxPhos defects are present in CRCs but not in APs. APs and CRCs tend to accumulate mtDNA mutations, but these are not correlated with bioenergetic profiles. Finally, the ALDOB and SLC16A4 may contribute to the glycolytic shift in APs/CRCs.
Identifiants
pubmed: 31122841
pii: S2352-3964(19)30339-1
doi: 10.1016/j.ebiom.2019.05.031
pmc: PMC6606928
pii:
doi:
Substances chimiques
Biomarkers
0
DNA, Mitochondrial
0
Monocarboxylic Acid Transporters
0
Muscle Proteins
0
SLC16A4 protein, human
0
Fluorodeoxyglucose F18
0Z5B2CJX4D
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
334-345Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.