Oncogenic targets Mmp7, S100a9, Nppb and Aldh1a3 from transcriptome profiling of FAP and Pirc adenomas are downregulated in response to tumor suppression by Clotam

Furkan U Ertem, Wenqian Zhang, Kyle Chang, Wan Mohaiza Dashwood, Praveen Rajendran, Deqiang Sun, Ala Abudayyeh, Eduardo Vilar, Maen Abdelrahim, Roderick H Dashwood

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Intervention strategies in familial adenomatous polyposis (FAP) patients and other high-risk colorectal cancer (CRC) populations have highlighted a critical need for endoscopy combined with safe and effective preventive agents. We performed transcriptome profiling of colorectal adenomas from FAP patients and the polyposis in rat colon (Pirc) preclinical model, and prioritized molecular targets for prevention studies in vivo. At clinically relevant doses in the Pirc model, the drug Clotam (tolfenamic acid, TA) was highly effective at suppressing tumorigenesis both in the colon and in the small intestine, when administered alone or in combination with Sulindac. Cell proliferation in the colonic crypts was reduced significantly by TA, coincident with increased cleaved caspase-3 and decreased Survivin, β-catenin, cyclin D1 and matrix metalloproteinase 7. From the list of differentially expressed genes prioritized by transcriptome profiling, Mmp7, S100a9, Nppb and Aldh1a3 were defined as key oncogene candidates downregulated in colon tumors after TA treatment. Monthly colonoscopies revealed the rapid onset of tumor suppression by TA in the Pirc model, and the temporal changes in Mmp7, S100a9, Nppb and Aldh1a3, highlighting their value as potential early biomarkers for prevention in the clinical setting. We conclude that TA, an "old drug" repurposed from migraine, offers an exciting new therapeutic avenue in FAP and other high-risk CRC patient populations.

Original languageEnglish (US)
Pages (from-to)460-468
Number of pages9
JournalInternational Journal of Cancer
Volume140
Issue number2
DOIs
StatePublished - Jan 15 2017

Keywords

  • Adenoma
  • Adenomatous Polyposis Coli
  • Aldehyde Oxidoreductases
  • Animals
  • Biomarkers, Tumor
  • Calgranulin B
  • Carcinogenesis
  • Caspase 3
  • Cell Proliferation
  • Colorectal Neoplasms
  • Cyclin D1
  • Down-Regulation
  • Gene Expression Profiling
  • Humans
  • Male
  • Matrix Metalloproteinase 7
  • Oncogenes
  • Rats
  • beta Catenin
  • ortho-Aminobenzoates
  • Journal Article

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