Regulation of genes in the arachidonic acid metabolic pathway by <scp>RNA</scp> processing and <scp>RNA</scp>‐mediated mechanisms

Lutz, Carol S.; Cornett, Ashley L.

doi:10.1002/wrna.1183

Cited by 22 publications

(14 citation statements)

References 126 publications

(172 reference statements)

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“…and ). The results indicate that 5‐LO activity is reduced following fracture, perhaps by signaling initiated by one or more of the rapidly‐induced inflammatory cytokines or through a coordinated gene expression regulatory mechanism . The results also suggest that 5‐LO and associated lipid mediators may function to mitigate the inflammatory response, serving perhaps as anti‐inflammatory mediators or as pro‐resolving mediators .…”

Section: Discussionmentioning

confidence: 88%

Variation in lipid mediator and cytokine levels during mouse femur fracture healing

Hao

Cottrell

O’Connor

2016

Journal Orthopaedic Research

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Fracture healing is regulated by a variety of inflammatory mediators and growth factors which act over time to regenerate the injured tissue. This study used a mouse femur fracture model to quantify the temporal expression pattern of lipid mediators, cytokines, and related mRNAs during healing. Cyclooxygenase (COX-1 and COX-2) and 5-lipoxygenase (5-LO) derived lipid mediators, cytokines, and mRNA levels were quantified using mass spectrometry (LC-MS/MS), bead-based multiplex assays (xMAP), and quantitative PCR of cDNA (RTqPCR), respectively. Our analysis found that, the early inflammatory response (between 0 and 4 days after fracture) in the mouse femur fracture model coincided with elevated levels of COX-derived lipid mediators and inflammatory cytokines but with decreased levels of 5-LO-derived lipid mediators. Further, the COX-derived lipid mediators remained elevated for at least 7 days after fracture, suggesting that the COX-derived lipid mediators have additional functions during later phases of the fracture healing response. Differences were also found between mRNA levels and corresponding cytokines and lipid mediator levels, supporting a role for post-transcriptional regulation of gene expression. The temporal changes in fracture callus lipid mediator levels and inflammatory cytokines support a general positive role for inflammatory cytokines and COX-derived lipid mediators on fracture healing and a general negative role for 5-lipoxygenase derived lipid mediators during the initial stages of repair. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1883-1893, 2016.

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Section: Discussionmentioning

confidence: 88%

Variation in lipid mediator and cytokine levels during mouse femur fracture healing

Hao

Cottrell

O’Connor

2016

Journal Orthopaedic Research

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“…Multiple forms of post-transcriptional regulation may be at play resulting in this disparity between FLAP mRNA and protein expression. There are two predicted splice variants of FLAP, both of which have the same 322 bp 3′ UTR (Figure 3A and [ 2 ]). Expression of the protein isoform of the second splice variant has yet to be experimentally validated.…”

Section: Resultsmentioning

confidence: 99%

“…COX-1 and COX-2 perform the same two enzymatic activities: oxidative cyclization and peroxidation of AA (2 and references therein). Our lab and others have demonstrated that COX-2 expression is regulated both transcriptionally and post-transcriptionally, including regulation by alternative polyadenylation of the COX-2 3′ untranslated region (3′ UTR) [ 16 , 17 ] and microRNA (miRNA)-mediated regulation by several different miRNAs in multiple cell types and tissues [ 2 , 18 , 19 ]. Most notable for the purposes of the current study is the miR-146a-mediated suppression of COX-2 in lung cancer cells, as we have previously shown [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

miR-146a suppresses 5-lipoxygenase activating protein (FLAP) expression and Leukotriene B4 production in lung cancer cells

2018

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Arachidonic acid (AA) can be converted into prostaglandins (PGs) or leukotrienes (LTs) by the enzymatic actions of cyclooxygenases (COX-1 and COX-2) or 5-lipoxygenase (5-LO), respectively. PGs and LTs are lipid signaling molecules that have been implicated in various diseases, including multiple cancers. 5-LO and its activating protein (FLAP) work together in the first two conversion steps of LT production. Previous work has suggested a role for LTs in cancer development and progression. MicroRNAs (miRNAs) are small RNA molecules that negatively regulate gene expression post-transcriptionally, and have previously been shown to be involved in cancer. Here, we show that high FLAP expression is associated with lower overall survival in lung adenocarcinoma patients, and FLAP protein is overexpressed in lung cancer cells compared to normal lung cells. Our lab has previously shown that miR-146a regulates COX-2 in lung cancer cells, and this miRNA is also predicted to target FLAP. Transient and stable transfections of miR-146a repress endogenous FLAP expression in lung cancer cells, and reporter assays show this regulation occurs through a direct interaction between the FLAP 3′ untranslated region (UTR) and miR-146a. Restoration of miR-146a also results in decreased cancer cell Leukotriene B4 (LTB4) production. Additionally, methylation analysis indicates the miR-146a promoter is hypermethylated in lung cancer cell lines. Taken together, this study and previous work from our lab suggest miR-146a is an endogenous dual inhibitor of AA metabolism in lung cancer cells by regulating both PG and LT production through direct targeting of the COX-2 and FLAP 3’ UTRs.

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“…It should be noted, however, that the concept of “constitutive” and “inducible” isoforms has been challenged by growing evidence indicating that both isoforms are present in normal tissues and can be up-regulated in various pathological conditions [21]. Both the expression and regulation of COX isoforms have been intensively investigated, and reviews about transcriptional regulatory mechanisms [22], and the regulation of gene expression at the co- or post-transcriptional level [23] have been recently published.…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase-1 (COX-1) and COX-1 Inhibitors in Cancer: A Review of Oncology and Medicinal Chemistry Literature

2018

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Prostaglandins and thromboxane are lipid signaling molecules deriving from arachidonic acid by the action of the cyclooxygenase isoenzymes COX-1 and COX-2. The role of cyclooxygenases (particularly COX-2) and prostaglandins (particularly PGE2) in cancer-related inflammation has been extensively investigated. In contrast, COX-1 has received less attention, although its expression increases in several human cancers and a pathogenetic role emerges from experimental models. COX-1 and COX-2 isoforms seem to operate in a coordinate manner in cancer pathophysiology, especially in the tumorigenesis process. However, in some cases, exemplified by the serous ovarian carcinoma, COX-1 plays a pivotal role, suggesting that other histopathological and molecular subtypes of cancer disease could share this feature. Importantly, the analysis of functional implications of COX-1-signaling, as well as of pharmacological action of COX-1-selective inhibitors, should not be restricted to the COX pathway and to the effects of prostaglandins already known for their ability of affecting the tumor phenotype. A knowledge-based choice of the most appropriate tumor cell models, and a major effort in investigating the COX-1 issue in the more general context of arachidonic acid metabolic network by using the systems biology approaches, should be strongly encouraged.

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Regulation of genes in the arachidonic acid metabolic pathway by RNA processing and RNA‐mediated mechanisms

Cited by 22 publications

References 126 publications

Variation in lipid mediator and cytokine levels during mouse femur fracture healing

Variation in lipid mediator and cytokine levels during mouse femur fracture healing

miR-146a suppresses 5-lipoxygenase activating protein (FLAP) expression and Leukotriene B4 production in lung cancer cells

Cyclooxygenase-1 (COX-1) and COX-1 Inhibitors in Cancer: A Review of Oncology and Medicinal Chemistry Literature

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