title: Role of NADPH oxidases in inducing a selective increase of oxidant stress and cyclin D1 and checkpoint 1 over-expression during progression to human gastric adenocarcinoma.
abstract: BACKGROUND
  Gastric cancer is one of the main causes of global mortality. Here, reactive oxygen species (ROS) could largely contribute to gastric carcinogenesis. Hence, the present work was aimed to assess the role of ROS, oxidant status, NADPH oxidases (NOXs) expression, during human gastric adenocarcinoma.
  
  
  METHODS
  We obtained subcellular fraction from samples of gastric mucosa taken from control subjects (n = 20), and from 40 patients with gastric adenocarcinoma, as well as samples of distant areas (tumour-free gastric mucosa).
  
  
  RESULTS
  Parameters indicative of lipid peroxidation and cell proliferation were selectively increased in both tumour-free and in cancerous gastric mucosa, despite of glutathione (GSH) content, glutathione reductase (GR) and superoxide dismutase (SOD) activities were increased in the adenocarcinoma. These high levels of antioxidant defences inversely correlated with down-regulated expression for NOX2 and 4; however, over-expression of NOX1 occurred with increased caspase-3 activity and overexpressed checkpoint 1 (MDC1) and cyclin D1 proteins. In the tumour-free mucosa an oxidant stress took place, without changing total GSH but with decreased activities for GR and mitochondrial SOD; moreover, over-expression of checkpoint 1 (MDC1) correlated with lower NOX2 and 4 expression in this mucosa.
  
  
  CONCLUSIONS
  Chronically injured gastric mucosa increases lipoperoxidative events and cell proliferation. In the adenocarcinoma, cell proliferation was further enhanced, oxidant stress decreased which seemed to be linked to NOX1, MDC1 and cyclin D1 over-expression, but with a lower NOXs activity leading a 'low tone' of ROS formation. Therefore, our results could be useful for early detection and treatment of gastric adenocarcinoma.
authors: Departamento de Cirugía, Facultad de Medicina, México 04510, D.F., Mexico; Servicio de Cirugía General, Unidad 304, Hospital General de México, México 04510, D.F., Mexico.
authors: Eduardo E
authors: EE
authors: Montalvo-Javé
authors: Biología Celular y Desarrollo, México 04510, D.F., Mexico.
authors: Marisela
authors: M
authors: Olguín-Martínez
authors: Neurodesarrollo y Fisiología, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), México 04510, D.F., Mexico.
authors: Diego R
authors: DR
authors: Hernández-Espinosa
authors: Biología Celular y Desarrollo, México 04510, D.F., Mexico.
authors: Lourdes
authors: L
authors: Sánchez-Sevilla
authors: Biología Celular y Desarrollo, México 04510, D.F., Mexico.
authors: Edgar
authors: E
authors: Mendieta-Condado
authors: Biología Celular y Desarrollo, México 04510, D.F., Mexico.
authors: Martha L
authors: ML
authors: Contreras-Zentella
authors: Departamento de Tumores de Tubo Digestivo, Instituto Nacional de Cancerología, México 04510, D.F., Mexico.
authors: Luis F
authors: LF
authors: Oñate-Ocaña
authors: Servicio de Cirugía General, Unidad 304, Hospital General de México, México 04510, D.F., Mexico.
authors: Tomás
authors: T
authors: Escalante-Tatersfield
authors: Servicio de Cirugía General, Unidad 304, Hospital General de México, México 04510, D.F., Mexico.
authors: Agustín
authors: A
authors: Echegaray-Donde
authors: Departamento de Tumores de Tubo Digestivo, Instituto Nacional de Cancerología, México 04510, D.F., Mexico.
authors: Juan M
authors: JM
authors: Ruiz-Molina
authors: Departamento de Cirugía, Instituto Nacional de Ciencias Médicas y Nutrición, México 04510, D.F., Mexico.
authors: Miguel F
authors: MF
authors: Herrera
authors: Neurodesarrollo y Fisiología, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), México 04510, D.F., Mexico.
authors: Julio
authors: J
authors: Morán
authors: Biología Celular y Desarrollo, México 04510, D.F., Mexico. Electronic address: rhernand@ifc.unam.mx.
authors: Rolando
authors: R
authors: Hernández-Muñoz
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D016022:Case-Control Studies; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D000071877:Checkpoint Kinase 1; D019938:Cyclin D1 / Q000378:metabolism*; D005260:Female; D005753:Gastric Mucosa / Q000201:enzymology; D006801:Humans; D008297:Male; D019255:NADPH Oxidases / Q000502:physiology*; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013274:Stomach Neoplasms / Q000201:enzymology*
chemical_list: D000975:Antioxidants; C530104:CCND1 protein, human; D016877:Oxidants; D017382:Reactive Oxygen Species; D019938:Cyclin D1; D019255:NADPH Oxidases; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; D020169:Caspases
keywords: Antioxidant defences; Apoptosis; Glutathione; NAD/NADH ratio; NOX1