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Preoperative low dose NSAID treatment influences the genes for stemness, growth, invasion and metastasis in colorectal cancer.

Lönnroth C, Andersson M, Asting AG, Nordgren S, Lundholm K - Int. J. Oncol. (2014)

Bottom Line: Concomittant to MHC locus activation, Prominin1/CD133, a marker associated with stemness and poor prognosis in several solid tumors, was downregulated.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).This is supported by the overall evaluation of gene expression profiles with subsequent events, indicating less aggressive tumors following NSAID treatment.

View Article: PubMed Central - PubMed

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.

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.

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Related in: MedlinePlus

Chromosomal map with (A) physical position view of microarray results with 2-fold up- or 2-fold downregulated genes, in tumors from indomethacin-treated vs. sham-treated control patients, visualized in GeneSpring program (Agilent). (B) Magnification with focus on chromosome 6p21 locus. Upregulated genes are red, downregulated genes are blue.
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f1-ijo-45-06-2208: Chromosomal map with (A) physical position view of microarray results with 2-fold up- or 2-fold downregulated genes, in tumors from indomethacin-treated vs. sham-treated control patients, visualized in GeneSpring program (Agilent). (B) Magnification with focus on chromosome 6p21 locus. Upregulated genes are red, downregulated genes are blue.

Mentions: Due to complex interactions between factors and signaling pathways as judged by visual inspection of files from microarray analyses, we also considered data with indicated different phenotypes of indomethacin-treated patients with support from results in other studies, as well as individually based Q-PCR analyses. Some altered genes belong to chromosome 6p21 or the extended MHC locus (xMHC), covering 7.6 Mb on the short arm of chromosome 6, represented by POLR1C and MAPK14/p38, as well as HIST1H2B1, belonging to a histone gene cluster containing 55 histone genes at 6p22-6p21 (Fig. 1). Together with other genes, they represent tumor markers, growth factors, growth factor receptors, oncogenes, tumor suppressor genes, glucose transporters and cytoskeletal genes (36,53–73) (Table V).


Preoperative low dose NSAID treatment influences the genes for stemness, growth, invasion and metastasis in colorectal cancer.

Lönnroth C, Andersson M, Asting AG, Nordgren S, Lundholm K - Int. J. Oncol. (2014)

Chromosomal map with (A) physical position view of microarray results with 2-fold up- or 2-fold downregulated genes, in tumors from indomethacin-treated vs. sham-treated control patients, visualized in GeneSpring program (Agilent). (B) Magnification with focus on chromosome 6p21 locus. Upregulated genes are red, downregulated genes are blue.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215588&req=5

f1-ijo-45-06-2208: Chromosomal map with (A) physical position view of microarray results with 2-fold up- or 2-fold downregulated genes, in tumors from indomethacin-treated vs. sham-treated control patients, visualized in GeneSpring program (Agilent). (B) Magnification with focus on chromosome 6p21 locus. Upregulated genes are red, downregulated genes are blue.
Mentions: Due to complex interactions between factors and signaling pathways as judged by visual inspection of files from microarray analyses, we also considered data with indicated different phenotypes of indomethacin-treated patients with support from results in other studies, as well as individually based Q-PCR analyses. Some altered genes belong to chromosome 6p21 or the extended MHC locus (xMHC), covering 7.6 Mb on the short arm of chromosome 6, represented by POLR1C and MAPK14/p38, as well as HIST1H2B1, belonging to a histone gene cluster containing 55 histone genes at 6p22-6p21 (Fig. 1). Together with other genes, they represent tumor markers, growth factors, growth factor receptors, oncogenes, tumor suppressor genes, glucose transporters and cytoskeletal genes (36,53–73) (Table V).

Bottom Line: Concomittant to MHC locus activation, Prominin1/CD133, a marker associated with stemness and poor prognosis in several solid tumors, was downregulated.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).This is supported by the overall evaluation of gene expression profiles with subsequent events, indicating less aggressive tumors following NSAID treatment.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus