Aurora kinase A promotes inflammation and tumorigenesis in mice and human gastric neoplasia.

Katsha A, Soutto M, Sehdev V, Peng D, Washington MK, Piazuelo MB, Tantawy MN, Manning HC, Lu P, Shyr Y, Ecsedy J, Belkhiri A, El-Rifai W
Gastroenterology. 2013 145 (6): 1312-22.e1-8

PMID: 23993973 · PMCID: PMC3840093 · DOI:10.1053/j.gastro.2013.08.050

BACKGROUND & AIMS - 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.

Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

MeSH Terms (23)

Adenocarcinoma Animals Aurora Kinase A Azepines Carcinogenesis Cell Line, Tumor Disease Models, Animal Female Gastric Mucosa Heterografts Humans Inflammation In Vitro Techniques Mice, Knockout Mice, Nude NF-kappa B Peptides Phosphorylation Protein Kinase Inhibitors Pyrimidines Stomach Neoplasms Trefoil Factor-1 Up-Regulation

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