Altered expression of mitochondrial cytochrome�c oxidase�I and NADH dehydrogenase�4 transcripts associated with gastric tumorigenesis and tumor dedifferentiation

Abstract

Abstract. This study aimed to detect the expression of mitochondrial mRNA in normal and cancerous gastric tissues and discuss their association with clinicopathological characteristics. Semi-quantitative reverse-transcription PCR was used to analyze mitochondrial transcripts in 42 cases of matched cancerous and normal gastric tissues. Expression of these genes was then statistically analyzed to determine the correlation with the clinicopathological characteristics from the patients. Transcripts of cytochrome c oxidase I (CO I) and NADH dehydrogenase 4 (ND4) were highly expressed in gastric cancer tissues compared to normal gastric tissues (P=0.005 and P=0.001, respectively). The expression levels of CO I and ND4 were higher in the diffused type of gastric cancer than in the intestinal type (P=0.024 and P=0.0002, respectively). Elevated expression of CO I and ND4 were associated with gastric tumorigenesis and tumor dedifferentiation ex vivo.

Mitochondrial genetics and therapeutic overview of Leber's hereditary optic neuropathy

“…Other diseases associated with mutation in the ND4 gene are Leigh syndrome, by affecting the CI activity;[ 43 ] cardiomyopathy, and MELAS due to mitochondrial dysfunction;[ 44 ] sporadic myopathy;[ 45 ] Parkinson's disease, has more mutation in the ND4 gene;[ 46 ] gastric cancer, has elevated expression of ND4 ;[ 47 ] oral cancer, due to mitochondrial dysfunction by mutation in ND4 ;[ 48 ] in acute myeloid leukemia, where the subjects had either germline or somatic ND4 mutations;[ 49 ] in blood and breast cancer, mutation in the protein coding regions of ND4 and other genes have been identified;[ 50 ] studies show that women with the G11778A mutation develop symptoms similar to multiple sclerosis which makes us to differentiate the disease that the patient actually has.…”

Tumor Metabolome Targeting and Drug Development

“…Consequently, differential expression of COX subunits, namely low expression of COXII and high expression of COXI and COXIII, was detected in hepatoma, colon, and prostate cancer [1,155,289]. High expression of COXI is also associated with gastric tumorigenesis and ex vivo de-differentiation [207], while mutations in COXI are associated with prostate cancer [241]. In 40 % of breast and ovarian tumors, a decrease in COX subunit II expression was identified [86].…”

“…Targeting Metabolic Enzymes Targeting hypoxia and the resultant stabilization of the HIF-1 complex is a viable approach to ameliorating the abnormal metabolism of cancer cells, but another approach is to directly influence the enzymes involved in glycolysis and anabolism that are the product of the hypoxic response [207,208]. Inhibition of GLUT-1 by the small molecule WBZ117 results in a decrease in cancer cell survival both in vitro and in vivo [209].…”

“…PFKFB3 is capable of being inhibited by 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3-PO), which has shown the ability in both in vitro and in vivo studies to reduce glycolytic flux and result in decreased disease progression in an animal model [218]. 3-bromopyruvate (3-BrPA) is a small molecule that was initially characterized as able to inhibit glycolysis, but it is currently unclear whether this is its only action [207]. Recent evidence indicates that MCT-1 is required for cellular uptake of 3-BrPA, but beyond that it is unclear that this compound only targets metabolic enzymes [219].…”

“…Taking advantage of the glycolytic phenotype, it is possible to induce acidosis of the malignant cells (decreasing intracellular pH [pH i ]) and prevent acidification of the tumor tissue (increasing extracellular pH [pH e ]) [207]. Frequently in hypoxic environments, cells adapt by upregulating glycolytic processes and concomitantly upregulating transporters that aid in detoxifying the cell of lactate and other acidic products of metabolism.…”