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

Ahmed Katsha, Mohammed Soutto, Vikas Sehdev, Dunfa Peng, M. Kay Washington, M. Blanca Piazuelo, Mohammed N. Tantawy, H. Charles Manning, Pengcheng Lu, Yu Shyr, Jeffrey Ecsedy, Abbes Belkhiri, Wael El-Rifai

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Abstract

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.

Original languageEnglish (US)
JournalGastroenterology
Volume145
Issue number6
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

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Keywords

  • Gene Regulation
  • Mouse Model
  • Stomach Cancer
  • TNF-α

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Katsha, A., Soutto, M., Sehdev, V., Peng, D., Washington, M. K., Piazuelo, M. B., Tantawy, M. N., Manning, H. C., Lu, P., Shyr, Y., Ecsedy, J., Belkhiri, A., & El-Rifai, W. (2013). Aurora kinase A promotes inflammation and tumorigenesis in mice and human gastric neoplasia. Gastroenterology, 145(6). https://doi.org/10.1053/j.gastro.2013.08.050