Oxidative Phosphorylation System in Gastric Carcinomas and Gastritis

Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have to Helicobacter pylori infection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas (“intestinal” and “diffuse”), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore, higher complex II and complex III protein levels were also obvious in grade 3 versus grade 2. No differences of OXPHOS complexes and markers of mitochondrial biogenesis were found between bacterially caused and chemically induced gastritis. Thus, intestinal gastric carcinomas, but not precancerous stages, are frequently characterized by loss of complex I, and this pathophysiology occurs independently of HP infection.

[1]  P. Navas,et al.  Coenzyme Q biosynthesis and its role in the respiratory chain structure. , 2016, Biochimica et biophysica acta.

[2]  Stephen L. Johnson,et al.  Lactate Metabolism is Associated with Mammalian Mitochondria , 2016, Nature chemical biology.

[3]  D. Czajkowsky,et al.  Complex clonal mosaicism within microdissected intestinal metaplastic glands without concurrent gastric cancer , 2016, Journal of Medical Genetics.

[4]  R. J. Gooding,et al.  Molecular characterization of Gleason patterns 3 and 4 prostate cancer using reverse Warburg effect-associated genes , 2016, Cancer & Metabolism.

[5]  S. Weis,et al.  Alterations of oxidative phosphorylation in meningiomas and peripheral nerve sheath tumors. , 2016, Neuro-oncology.

[6]  Li Zhang,et al.  A holistic view of cancer bioenergetics: mitochondrial function and respiration play fundamental roles in the development and progression of diverse tumors , 2016, Clinical and Translational Medicine.

[7]  H. Prokisch,et al.  Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype , 2015, Orphanet Journal of Rare Diseases.

[8]  Wei Zhang,et al.  Mutational landscape of gastric adenocarcinoma in Chinese: Implications for prognosis and therapy , 2015, Proceedings of the National Academy of Sciences.

[9]  M. Rauh,et al.  HIBCH deficiency in a patient with phenotypic characteristics of mitochondrial disorders , 2014, American journal of medical genetics. Part A.

[10]  E. Bollschweiler,et al.  Pathohistological classification systems in gastric cancer: diagnostic relevance and prognostic value. , 2014, World journal of gastroenterology.

[11]  S. Weis,et al.  Alterations of oxidative phosphorylation complexes in astrocytomas , 2014, Glia.

[12]  N. Jones,et al.  Modulation of autophagy by Helicobacter pylori and its role in gastric carcinogenesis. , 2013, Trends in microbiology.

[13]  L. Rasmussen,et al.  Helicobacter pylori infection affects mitochondrial function and DNA repair, thus, mediating genetic instability in gastric cells , 2013, Mechanisms of Ageing and Development.

[14]  Nayoung Kim,et al.  Long-term follow up Helicobacter Pylori reinfection rate after second-line treatment: bismuth-containing quadruple therapy versus moxifloxacin-based triple therapy , 2013, BMC Gastroenterology.

[15]  F. Chiaradonna,et al.  Mitochondrial Complex I Inhibitors and Forced Oxidative Phosphorylation Synergize in Inducing Cancer Cell Death , 2013, International journal of cell biology.

[16]  Chang-ming Huang,et al.  Tumor size as a prognostic factor in patients with advanced gastric cancer in the lower third of the stomach. , 2012, World journal of gastroenterology.

[17]  M. Kim,et al.  Tumor Size as a Prognostic Factor in Gastric Cancer Patient , 2012, Journal of gastric cancer.

[18]  T. Kwok,et al.  Vacuolating cytotoxin A (VacA), a key toxin for Helicobacter pylori pathogenesis , 2012, Front. Cell. Inf. Microbio..

[19]  Jenn-Kang Hwang,et al.  Computational analysis of a novel mutation in ETFDH gene highlights its long-range effects on the FAD-binding motif , 2011, BMC Structural Biology.

[20]  Prashant Jain,et al.  Helicobacter pylori vacuolating cytotoxin A (VacA) engages the mitochondrial fission machinery to induce host cell death , 2011, Proceedings of the National Academy of Sciences.

[21]  M. Piazuelo,et al.  Helicobacter pylori Infection and Gastric Adenocarcinoma. , 2011, US gastroenterology & hepatology review.

[22]  Li-li Huang,et al.  Helicobacter pylori induces mitochondrial DNA mutation and reactive oxygen species level in AGS cells , 2011, International journal of medical sciences.

[23]  A. Galmiche,et al.  Targeting of Helicobacter pylori VacA to mitochondria , 2010, Gut microbes.

[24]  T. Lithgow,et al.  Both the p33 and p55 subunits of the Helicobacter pylori VacA toxin are targeted to mammalian mitochondria. , 2010, Journal of Molecular Biology.

[25]  D. Merrell,et al.  A Tale of Two Toxins: Helicobacter Pylori CagA and VacA Modulate Host Pathways that Impact Disease , 2010, Front. Microbio..

[26]  C. Chaumontet,et al.  Oxidation of hydrogen sulfide remains a priority in mammalian cells and causes reverse electron transfer in colonocytes. , 2010, Biochimica et biophysica acta.

[27]  N. Jones,et al.  Low aerobic mitochondrial energy metabolism in poorly- or undifferentiated neuroblastoma , 2010, BMC Cancer.

[28]  C. Chi,et al.  Somatic mutations in mitochondrial genome and their potential roles in the progression of human gastric cancer. , 2010, Biochimica et biophysica acta.

[29]  P. Fortina,et al.  The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma , 2009, Cell cycle.

[30]  F. Lindbichler,et al.  A novel mutation of the RRM2B gene in an infant with early fatal encephalomyopathy, central hypomyelination, and tubulopathy. , 2009, Molecular genetics and metabolism.

[31]  L. Rasmussen,et al.  Helicobacter pylori Infection Induces Genetic Instability of Nuclear and Mitochondrial DNA in Gastric Cells , 2009, Clinical Cancer Research.

[32]  A. Witkowski,et al.  Down-regulation of Mitochondrial Acyl Carrier Protein in Mammalian Cells Compromises Protein Lipoylation and Respiratory Complex I and Results in Cell Death* , 2009, Journal of Biological Chemistry.

[33]  B. Alinger,et al.  Lack of complex I is associated with oncocytic thyroid tumours , 2009, British Journal of Cancer.

[34]  T. Cover,et al.  Helicobacter pylori VacA Disrupts Apical Membrane-Cytoskeletal Interactions in Gastric Parietal Cells* , 2008, Journal of Biological Chemistry.

[35]  J. Lieberman,et al.  Granzyme A Cleaves a Mitochondrial Complex I Protein to Initiate Caspase-Independent Cell Death , 2008, Cell.

[36]  D. Meierhofer,et al.  Loss of Complex I due to Mitochondrial DNA Mutations in Renal Oncocytoma , 2008, Clinical Cancer Research.

[37]  Giovanni Romeo,et al.  Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors , 2007, Proceedings of the National Academy of Sciences.

[38]  T. Borén,et al.  Helicobacter pylori is invasive and it may be a facultative intracellular organism , 2007, Cellular microbiology.

[39]  R. Fiocca,et al.  Intracellular, intercellular, and stromal invasion of gastric mucosa, preneoplastic lesions, and cancer by Helicobacter pylori. , 2007, Gastroenterology.

[40]  F. Bussière,et al.  Low multiplicity of infection of Helicobacter pylori suppresses apoptosis of B lymphocytes. , 2006, Cancer research.

[41]  K. Tsuneyama,et al.  Pathobiological characteristics of intestinal and diffuse-type gastric carcinoma in Japan: an immunostaining study on the tissue microarray , 2006, Journal of Clinical Pathology.

[42]  J. Gisbert,et al.  Recurrence of Helicobacter pylori infection after several eradication therapies: long‐term follow‐up of 1000 patients , 2006, Alimentary pharmacology & therapeutics.

[43]  K. Chayama,et al.  Somatic mutations of mitochondrial DNA in digestive tract cancers , 2005, Journal of gastroenterology and hepatology.

[44]  T. Cover,et al.  Helicobacter pylori VacA, a paradigm for toxin multifunctionality , 2005, Nature Reviews Microbiology.

[45]  John R. Mackey,et al.  Gastric Adenocarcinoma: Review and Considerations for Future Directions , 2005, Annals of surgery.

[46]  Mark H Ellisman,et al.  Disruption of Mitochondrial Function during Apoptosis Is Mediated by Caspase Cleavage of the p75 Subunit of Complex I of the Electron Transport Chain , 2004, Cell.

[47]  K. Chayama,et al.  Somatic mutation of mitochondrial DNA in Helicobacter pylori-associated chronic gastritis in patients with and without gastric cancer. , 2003, International journal of molecular medicine.

[48]  D. Marsh,et al.  Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas , 2003, Oncogene.

[49]  S. Falkow,et al.  Helicobacter pylori enter and survive within multivesicular vacuoles of epithelial cells , 2002, Cellular microbiology.

[50]  C. Kisker,et al.  Isolated sulfite oxidase deficiency: identification of 12 novel SUOX mutations in 10 patients , 2002, Human mutation.

[51]  F. Macrae,et al.  Selective colonization by Helicobacter pylori of the deep gastric glands and intracellular canaliculi of parietal cells in the setting of chronic proton pump inhibitor use. , 2002, European journal of gastroenterology & hepatology.

[52]  R. Seruca,et al.  Microsatellite instability, mitochondrial DNA large deletions, and mitochondrial DNA mutations in gastric carcinoma , 2001, Genes, chromosomes & cancer.

[53]  E S Husebye,et al.  Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. , 2001, American journal of human genetics.

[54]  L. David,et al.  Clinicopathologic Profiles and Prognosis of Gastric Carcinomas from the Cardia, Fundus/Body and Antrum , 2001, Digestive Surgery.

[55]  N. Bianchi,et al.  Mitochondrial genome instability in human cancers. , 2001, Mutation research.

[56]  M F Dixon,et al.  Histological identification of Helicobacter pylori: comparison of staining methods , 2000, Journal of clinical pathology.

[57]  N. Uesugi,et al.  Microsatellite instability and mutation of mitochondrial and nuclear DNA in gastric carcinoma. , 2000, Gastroenterology.

[58]  J. V. van Sandick,et al.  Prognostic Value of Laurén Classification and c-erbB-2 Oncogene Overexpression in Adenocarcinoma of the Esophagus and Gastroesophageal Junction , 1999, Annals of Surgical Oncology.

[59]  G. Brooks,et al.  Mammalian fuel utilization during sustained exercise. , 1998, Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology.

[60]  S. Meltzer,et al.  Helicobacter pylori stimulates inducible nitric oxide synthase expression and activity in a murine macrophage cell line. , 1996, Gastroenterology.

[61]  S. Badve,et al.  Helicobacter pylori infection density and gastric inflammation in duodenal ulcer and non-ulcer subjects. , 1995, Gut.

[62]  M. Blaser,et al.  Purification and characterization of the vacuolating toxin from Helicobacter pylori. , 1992, The Journal of biological chemistry.

[63]  P. Laurén,et al.  THE TWO HISTOLOGICAL MAIN TYPES OF GASTRIC CARCINOMA: DIFFUSE AND SO-CALLED INTESTINAL-TYPE CARCINOMA. AN ATTEMPT AT A HISTO-CLINICAL CLASSIFICATION. , 1965, Acta pathologica et microbiologica Scandinavica.

[64]  Otto Warburn,et al.  THE METABOLISM OF TUMORS , 1931 .

[65]  O. Warburg.  über den Stoffwechsel der Carcinomzelle , 1925, Klinische Wochenschrift.

[66]  Muh-Hwa Yang,et al.  Clinicopathological Variation of Lauren Classification in Gastric Cancer , 2015, Pathology & Oncology Research.

[67]  Ping-li,et al.  Tumor size as a prognostic factor in patients with advanced gastric cancer in the lower third of the stomach , 2012 .

[68]  F. Berthold,et al.  Loss of mitochondria in ganglioneuromas. , 2011, Frontiers in bioscience.

[69]  K. Sargsyan,et al.  Respiratory chain complex I is a mitochondrial tumor suppressor of oncocytic tumors. , 2011, Frontiers in bioscience.

[70]  S. Teramukai,et al.  Intracellular VacA Is a Valuable Marker to Predict Whether Helicobacter pylori Induces Progressive Atrophic Gastritis That Is Associated with the Development of Gastric Cancer , 2005, Digestive Diseases and Sciences.

[71]  M. Blaser,et al.  Helicobacter pylori and gastrointestinal tract adenocarcinomas , 2002, Nature Reviews Cancer.

[72]  G. Kovacs,et al.  Analysis of Differentially Expressed Mitochondrial Proteins in Chromo- Phobe Renal Cell Carcinomas and Renal Oncocytomas by 2-d Gel Electro- Phoresis , 2022 .