Abstract
Objective:Colorectal cancer (CRC) develops from precancerous adenomatous polyps to malignant lesions of adenocarcinoma. Elucidating inhibition mechanisms for this route in patients with a risk of developing CRC is highly important for a potential diagnostic or prognostic marker. Differential expression of nuclear-encoded cytochrome c oxidase subunit 4 (COXIV) seems to contribute to a more unregulated respiration due to loss of ATP inhibition. Majority of energy for tumor transformations are mitochondrial origin. Differences in mitochondrial efficiency may be reflected in the progression of colorectal adenomatous polyps to adenocarcinomas. Here, we evaluate expression levels of COXIV isoform 1 (COXIV-1) and Mitochondrial (MT)-ATP synthase Subunit 6 (ATPase6) in adenomas of tubular, tubulovillous and villous tissues as compared to adenocarcinoma tissues.Method:Both RT-qPCR and western blot techniques were used to assess COXIV-1 and ATPase6 expression levels in 42 pairs of patients’ tissue samples. Protein carbonyl assay was performed to determine levels of oxidized proteins, as a measurement of ROS productions, in the tissue samples.Results:Differential RNA expression levels of COXIV-1 and ATPase6 from whole tissues were observed. Interestingly, RNA expression levels obtained from mitochondrial for COXIV-1 were significantly decreased in tubulovillous, villous adenomas and adenocarcinoma, but not in the tubular-polyps. Moreover, mitochondrial ATPase6 RNA expression levels decreased progressively from adenopolyps to adenocarcinoma. In mitochondrial protein, expression levels of both genes progressively decreased with a three folds from adenomatous polyps to adenocarcinoma. Whilst the ATPase6 protein expression significantly decreased in adenocarcinoma compared to villous, conversely, the levels of oxidized carbonyl proteins were considerably increased from adenomatous polyps to adenocarcinoma.Conclusion:Our findings provide evidence that decreased mitochondrial protein expression of COXIV-1 and ATPase6 correlates with increased ROS production during colorectal adenomatous polyps’ progression, suggesting the pivotal role of COXIV-1 in energy metabolism of colorectal cells as they progress from polyps to carcinoma.
Highlights
Despite great improvement in the treatment of colorectal cancer (CRC), this disease is still one of the most common malignancies worldwide and the third leading cause of cancerrelated death in the United States [1,2]
RNA expression levels obtained from mitochondrial for COXIV isoform 1 (COXIV-1) were significantly decreased in tubulovillous, villous adenomas and adenocarcinoma, but not in the tubular-polyps
Expression levels of both genes progressively decreased with a three folds from adenomatous polyps to adenocarcinoma
Summary
Despite great improvement in the treatment of colorectal cancer (CRC), this disease is still one of the most common malignancies worldwide and the third leading cause of cancerrelated death in the United States [1,2]. Most of the proteins that reside in the mitochondrion are nuclear gene products and these proteins are translated in the cytoplasmic compartment of eukaryotic cells and post-translationally, transported into the mitochondrion [6]. These proteins are involved in mitochondrial transcription, translation, mitochondrial lipid and heme synthesis; substrate oxidation by the Krebs cycle, electron transport and oxidative phosphorylation of the mitochondria. Regulation of OXPHOS and control of ROS production occurs due to proton slip at COX, allowing electrons to reduce oxygen without concomitant pumping of protons to the inter-membrane space thereby lowering mitochondrial efficiency [9,10]. Given that COXIV-1 is responsible for allosteric regulation of COX activity via binding sites for both ADP and ATP, where the ATP/ADP ratio regulates its activity [11], a different expression of COXIV-1 may have impact on the mitochondrial
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