title: Preoperative low dose NSAID treatment influences the genes for stemness, growth, invasion and metastasis in colorectal cancer.
abstract: Preclinical data, and an increasing list of clinical investigations, show anti-inflammatory agents to favourably influence the biology of colorectal tumor. We have earlier reported on re-expression of activated immune cells after three days preoperative treatment of patients with colorectal carcinoma, randomized to receive oral NSAID (indomethacin or celebrex). Antisecretory prophylaxis (esomeprasol) was provided to all patients and served as sham treatment. Concomittant to MHC locus activation, Prominin1/CD133, a marker associated with stemness and poor prognosis in several solid tumors, was downregulated. The aim of the present study was to evaluate expression of additional regulators belonging to the stem cell niche, OCT4, SOX2 and BMP7, as well as some microRNAs, reported to act as tumor suppressors or oncomiRs. Peroperative tumor biopsies were analyzed by microarrays, quantitative real-time PCR and immunohistochemistry (IHC). The stem cell master regulator SOX2 was increased by NSAIDs (p<0.01), as well as the tumor suppressor miR-630 (p<0.01), while BMP7, a marker for poor prognosis in CRC, was downregulated by NSAID (indomethacin, p<0.02). The upregulation of SOX2, but not of its heterodimer binding partner OCT4, could imply a negative feed-back loop, with a switch‑off for stemness preservation of tumor cells. This is supported by the overall evaluation of gene expression profiles with subsequent events, indicating less aggressive tumors following NSAID treatment.
authors.affiliation: Department of Surgery, Surgical Metabolic Research Laboratory at Lundberg Laboratory for Cancer Research, Sahlgrenska University Hospital, University of Gothenburg, SE 413 45 Gothenburg, Sweden.
authors.forename: Christina
authors.initials: C
authors.lastname: Lönnroth
authors.affiliation: Department of Surgery, Surgical Metabolic Research Laboratory at Lundberg Laboratory for Cancer Research, Sahlgrenska University Hospital, University of Gothenburg, SE 413 45 Gothenburg, Sweden.
authors.forename: Marianne
authors.initials: M
authors.lastname: Andersson
authors.affiliation: Department of Surgery, Surgical Metabolic Research Laboratory at Lundberg Laboratory for Cancer Research, Sahlgrenska University Hospital, University of Gothenburg, SE 413 45 Gothenburg, Sweden.
authors.forename: Annika G
authors.initials: AG
authors.lastname: Asting
authors.affiliation: Department of Surgery, Surgical Metabolic Research Laboratory at Lundberg Laboratory for Cancer Research, Sahlgrenska University Hospital, University of Gothenburg, SE 413 45 Gothenburg, Sweden.
authors.forename: Svante
authors.initials: S
authors.lastname: Nordgren
authors.affiliation: Department of Surgery, Surgical Metabolic Research Laboratory at Lundberg Laboratory for Cancer Research, Sahlgrenska University Hospital, University of Gothenburg, SE 413 45 Gothenburg, Sweden.
authors.forename: Kent
authors.initials: K
authors.lastname: Lundholm
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000235:genetics; D000068579:Celecoxib; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage*; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D009362:Neoplasm Metastasis; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis; D011379:Prognosis; D011720:Pyrazoles / Q000008:administration & dosage*; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis; D013449:Sulfonamides / Q000008:administration & dosage*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D014408:Biomarkers, Tumor; D035683:MicroRNAs; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D011720:Pyrazoles; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D013449:Sulfonamides; D000068579:Celecoxib; D007213:Indomethacin