title: Aurora kinase A promotes inflammation and tumorigenesis in mice and human gastric neoplasia.
abstract: OBJECTIVE
  Chronic inflammation contributes to the pathogenesis of gastric tumorigenesis. The aurora kinase A (AURKA) gene is frequently amplified and overexpressed in gastrointestinal cancers. We investigated the roles of AURKA in inflammation and gastric tumorigenesis.
  
  
  METHODS
  We used quantitative real-time reverse transcription polymerase chain reaction, immunofluorescence, immunohistochemistry, luciferase reporter, immunoblot, co-immunoprecipitation, and in vitro kinase assays to analyze AGS and MKN28 gastric cancer cells. We also analyzed Tff1(-/-) mice, growth of tumor xenografts, and human tissues.
  
  
  RESULTS
  We correlated increased expression of AURKA with increased levels of tumor necrosis factor-α and inflammation in the gastric mucosa of Tff1(-/-) mice (r = 0.62; P = .0001). MLN8237, an investigational small-molecule selective inhibitor of AURKA, reduced nuclear staining of nuclear factor-κB (NF-κB) p65 in human gastric cancer samples and mouse epithelial cells, suppressed NF-κB reporter activity, and reduced expression of NF-κB target genes that regulate inflammation and cell survival. Inhibition of AURKA also reduced growth of xenograft tumors from human gastric cancer cells in mice and reversed the development of gastric tumors in Tff1(-/-) mice. AURKA was found to regulate NF-κB activity by binding directly and phosphorylating IκBα in cells. Premalignant and malignant lesions from the gastric mucosa of patients had increased levels of AURKA protein and nuclear NF-κB, compared with healthy gastric tissue.
  
  
  CONCLUSIONS
  In analyses of gastric cancer cell lines, human tissue samples, and mouse models, we found AURKA to be up-regulated during chronic inflammation to promote activation of NF-κB and tumorigenesis. AURKA inhibitors might be developed as therapeutic agents for gastric cancer.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Katsha
authors.forename: Mohammed
authors.initials: M
authors.lastname: Soutto
authors.forename: Vikas
authors.initials: V
authors.lastname: Sehdev
authors.forename: Dunfa
authors.initials: D
authors.lastname: Peng
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: M Blanca
authors.initials: MB
authors.lastname: Piazuelo
authors.forename: Mohammed N
authors.initials: MN
authors.lastname: Tantawy
authors.forename: H Charles
authors.initials: HC
authors.lastname: Manning
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Lu
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ecsedy
authors.forename: Abbes
authors.initials: A
authors.lastname: Belkhiri
authors.forename: Wael
authors.initials: W
authors.lastname: El-Rifai
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D001381:Azepines / Q000494:pharmacology; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D064593:Heterografts; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000378:metabolism*; D018345:Mice, Knockout; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D010455:Peptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D000071163:Trefoil Factor-1; D015854:Up-Regulation
chemical_list: D001381:Azepines; C550258:MLN 8237; D016328:NF-kappa B; D010455:Peptides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C472724:Tff1 protein, mouse; D000071163:Trefoil Factor-1; D064096:Aurora Kinase A
keywords: AURKA; Aurora kinase A; Gene Regulation; Mouse Model; NF-κB; Stomach Cancer; TNF; TNF-α; mRNA; messenger RNA; nuclear factor κB; tumor necrosis factor