Celecoxib Treatment Alters the Gene Expression Profile of Normal Colonic Mucosa

Glebov, O K; Rodríguez, Luz M.; Lynch, Patrick M.; Patterson, Sherri; Lynch, Henry T.; Nakahara, Kenneth; Jenkins, Jean; Cliatt, Janet; Humbyrd, Casey Jo; Denobile, John; Soballe, Peter W.; Gallinger, Steven; Buchbinder, Aby; Gordon, Gary; Hawk, Ernest T.; Kirsch, Ilan R.

doi:10.1158/1055-9965.epi-04-0866

Cited by 41 publications

(39 citation statements)

References 75 publications

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“…In conclusion, the present clinical findings emphasized that prostanoid metabolism is complex in colon cancer tissue and involves several hundred genes, which appear to control local tumor growth and net immune response (20,42), cell proliferation, differentiation, energy metabolism and apoptosis as earlier reported for normal colon tissue (41). However, alterations in tumor tissue gene expression following indomethacin treatment were not entirely similar to alterations in normal colon tissue from the same patients or to findings in cultured colon cancer cell lines.…”

Section: Discussionsupporting

confidence: 78%

“…Our purpose with gene profiling was to map appearance/disappearance of gene transcripts in relationship to high and low PGE 2 content in tumor tissue despite tumor stage, as earlier reported for normal colon tissue after longterm treatment with celecoxib (41). Similarly, an earlier report from our group displayed impacts on HLA antigen expression including markers for immune defense reactions (20), in agreement with a report by Auman et al who pretreated patients with celecoxib for 7 days and found evidence of increased immune response (42).…”

Section: Discussionmentioning

confidence: 99%

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Receptor and enzyme expression for prostanoid metabolism in colorectal cancer related to tumor tissue PGE2

Gustafsson

Andersson²,

Lagerstedt³

et al. 2009

Int J Oncol

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Abstract. Prostaglandins support progression of colorectal cancer by several mechanisms. This conclusion is based on epidemiological and drug intervention long-term studies or retrieved from animal and cell culture experiments. The aim of the present study was to map receptor and enzyme expression for prostanoid metabolism in the presence of high or low PGE 2 content within colon cancer tissue at primary tumor operation and after short-term preoperative provision of non-steroidal anti-inflammatory drug (NSAID). Twentythree unselected patients with colon cancer were randomly selected to receive indomethacin (NSAID) or sham treatment for 3 days before surgery. Normal colon and tumor tissue were collected at operation for RNA extraction. Tissue PGE 2 levels were measured by radioimmunoassay. Gene expression was quantified by microarray and real-time PCR. COX-1 expression increased proportionally to COX-2 expression in colon cancer tissue from untreated patients. Indomethacin reduced PGE 2 content in normal and tumor tissue with subsequently decreased IP, HPGD and PPARÁ receptor expression in both tumor and normal colon tissue, while subtype EP 1-4 receptors were not significantly influenced by indomethacin treatment. MPGES-1 expression was not related to overall PGE 2 content in tumor and colon tissue, but decreased significantly in normal tissue during indomethacin exposure. Reduction of tumor tissue PGE 2 was related to significant alteration in expression of several hundred genes indicating decreased cell cycling and increased apoptosis during indomethacin treatment, probably related to upregulation of acute phase reactants in tumor tissue. Increased prostanoid activity in colon cancer tissue is related to cross-talk between tumor and stroma cells.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Receptor and enzyme expression for prostanoid metabolism in colorectal cancer related to tumor tissue PGE2

Gustafsson

Andersson²,

Lagerstedt³

et al. 2009

Int J Oncol

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“…Previously, differential proteomic and transcriptomic profiling in colorectal cancer cell lines and healthy colonic mucosa of patients with hereditary nonpolyposis colon cancer, respectively, have shown celecoxib-mediated expression changes in diverse cellular functions, including cell proliferation, apoptosis, immune function, and cell signaling (18,19). In this investigation, we have performed transcription profiling of colorectal cancer cells to gain an unbiased global perspective of molecular networks and pathways targeted by celecoxib.…”

Section: Introductionmentioning

confidence: 99%

Altered Gene Expression Profiles Define Pathways in Colorectal Cancer Cell Lines Affected by Celecoxib

Yi¹,

Ajaz²,

Stephens³

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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It is well established that celecoxib, a selective inhibitor of cyclooxygenase-2 (COX-2) and a tested chemopreventive agent, has several COX-2 -independent activities. In an attempt to better understand COX-2 -independent molecular mechanisms underlying the chemopreventive activity of celecoxib, we did global transcription profiling of celecoxib-treated COX-2 -positive and COX-2 -deficient colorectal cancer cell lines. Celecoxib treatment resulted in significantly altered expression levels of over 1,000 to 3,000 transcripts in these cell lines, respectively. A pathway/functional analysis of celecoxib-affected transcripts, using Gene Ontology and Biocarta Pathways and exploring biological association networks, revealed that celecoxib modulates expression of numerous genes involved in a variety of cellular processes, including metabolism, cell proliferation, apoptotic signaling, cell cycle check points, lymphocyte activation, and signaling pathways. Among these processes, cell proliferation and apoptotic signaling consistently ranked as the highest-scoring Gene Ontology terms and Biocarta Pathways in both COX-2 expresser and nonexpresser cell lines. Altered expression of many of the genes by celecoxib was confirmed by quantitative PCR and at the protein level by Western blotting. Many novel genes emerged from our analysis of global transcription patterns that were not previously reported to be affected by celecoxib. In the future, in-depth work on selected genes will determine if these genes may serve as potential molecular targets for more effective chemopreventive

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“…GC-rich sequence DNA-binding factor (GCFC2) factor were found to be differentially expressed in celecoxib treated hereditary nonpolyposis colon cancer patient cells 187 . GCFC2 was also found to be down regulated after the treatment of ETC-1922159 in colorectal cancer cells 51 .…”

Section: Dicationmentioning

confidence: 99%

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

Sinha¹

2017

Preprint

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WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. WNTs have been found to directly affect the stemness of the tumor cells via regulation of ASCL2. Switching off the ASCL2 literally blocks the stemness process of the tumor cells and vice versa. Furthermore, recent findings suggest BVES to be highly suppressed in malignancies and in vitro deletions of BVES show higher Wnt signaling activity to induce stemness. WNT10B was found to be highly expressed in such cases. Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. For example, WNT10B-ASCL2 is one such 2 nd order combination whose relation needs to be tested under the influence of recently developed porcupine-WNT inhibitor ETC-1922159. The inhibitor is known to suppress PORCN (porcupine) and thus inhibit a range of oncogenes known to be directly or indirectly affected by the Wnts. In a recent unpublished work in bioRxiv, Sinha 1 , we had the opportunity to rank these unknown biological hypotheses for down regulated genes at 2 nd order level after the drug was administered. The in silico observations showed that the combination of WNT10B-ASCL2 was assigned a relatively lower rank, thus validating the pipeline's efficacy with the confirmed wet lab experiment that indicate that both WNT10B and ASCL2 were down regulated after treatment in cancer cells. Here, we take one step further by in silico analysis of the 3 rd order combinations of WNT10B-X-X (X can be known or unknown factor), from a range of 100 randomly picked down regulated genes after ETC-1922159 treatment. The pipeline uses the density based HSIC (Hilbert Schmidt Information Criterion) sensitivity index with an rbf (radial basis function) kernel, which is known to be highly effective in sensitivity analysis. Various unknown/unexplored/untested 3 rd order biological hypotheses emerge some of which are confirmed in wet lab, while others need to be tested. The potential of such ranking is indispensable in the current era of search in a vast combinatorial forest. KEYWORDS -WNT pathway; porcupine inhibitor ETC-1922159; sensitivity analysis; colorectal cancer; unknown biological hypotheses; combinatorial search space; support vector ranking Conference, from 6-11 August 2017, held Significance WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. Often, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be involved in the pathway. The current work reveals at in silico level, the 3rd order WNT10B associated combinations that might be affected by the admin...

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Celecoxib Treatment Alters the Gene Expression Profile of Normal Colonic Mucosa

Abstract: A clinical trial was recently conducted to evaluate the safety and efficacy of a selective inhibitor of cyclooxygenase-2

Cited by 41 publications

References 75 publications

Receptor and enzyme expression for prostanoid metabolism in colorectal cancer related to tumor tissue PGE2

Receptor and enzyme expression for prostanoid metabolism in colorectal cancer related to tumor tissue PGE2

Altered Gene Expression Profiles Define Pathways in Colorectal Cancer Cell Lines Affected by Celecoxib

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

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