Dynamic bioenergetic alterations in colorectal adenomatous polyps and adenocarcinomas

被引：25

作者：

Lin, Wey-Ran ^{[1
,2
,7
]}

Chiang, Jy-Ming ^{[3
]}

Lim, Siew-Na ^{[4
]}

Su, Ming-Yao ^{[1
,2
]}

Chen, Tsung-Hsing ^{[1
,2
]}

Huang, Shu-Wei ^{[1
]}

Chen, Chun-Wei ^{[1
]}

Wu, Ren-Chin ^{[5
]}

Tsai, Chia-Lung ^{[6
]}

Lin, Yang-Hsiang ^{[2
,7
]}

Alison, Malcolm R. ^{[8
]}

Hsieh, Sen-Yung ^{[1
,2
]}

Yu, Jau-Song ^{[9
]}

Chiu, Cheng-Tang ^{[1
,2
]}

Yeh, Chau-Ting ^{[1
,2
,7
]}

机构：

[1] Linkou Chang Gung Mem Hosp, Dept Gastroenterol & Hepatol, 5 Fu Shin St, Taoyuan 333, Taiwan

[2] Chang Gung Univ, Coll Med, Taoyuan, Taiwan

[3] Linkou Chang Gung Mem Hosp, Dept Proctol, Taoyuan, Taiwan

[4] Linkou Chang Gung Mem Hosp, Dept Neurol, Taoyuan, Taiwan

[5] Linkou Chang Gung Mem Hosp, Dept Pathol, Taoyuan, Taiwan

[6] Linkou Chang Gung Mem Hosp, Genom Med Res Core Lab, Taoyuan, Taiwan

[7] Linkou Chang Gung Mem Hosp, Liver Res Ctr, Taoyuan, Taiwan

[8] Queen Mary Univ London, Barts Canc Inst, London, England

[9] Chang Gung Univ, Coll Med, Grad Inst Biomed Sci, Taoyuan, Taiwan

来源：

EBIOMEDICINE | 2019年 / 44卷

关键词：

Bioenergetics; Mitochondrial oxidative phosphorylation; Glycolysis; Colorectal adenomatous polyp; Colorectal cancer; INFLAMMATORY-BOWEL-DISEASE; MITOCHONDRIAL-DNA MUTATIONS; OXIDATIVE STRESS; CELL-PROLIFERATION; CANCER; METABOLISM; INSTABILITY; PROGRESSION; IMPAIRMENT; EXPRESSION;

D O I：

10.1016/j.ebiom.2019.05.031

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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: 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: 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: 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. (C) 2019 The Authors. Published by Elsevier B.V.

引用

页码：334 / 345

页数：12

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