MicroRNA and AU-rich element regulation of prostaglandin synthesis.

Many lines of evidence demonstrate that prostaglandins play an important role in cancer, and enhanced synthesis of prostaglandin E(2) (PGE(2)) is often observed in various human malignancies often associated with poor prognosis. PGE(2) synthesis is initiated with the release of arachidonic acid by phospholipase enzymes, where it is then converted into the intermediate prostaglandin prostaglandin H(2) (PGH(2)) by members of the cyclooxygenase family. The synthesis of PGE(2) from PGH(2) is facilitated by three different PGE synthases, and functional PGE(2) can promote tumor growth by binding to four EP receptors to activate signaling pathways that control cell proliferation, migration, apoptosis, and angiogenesis. An integral method of controlling gene expression is by posttranscriptional mechanisms that regulate mRNA stability and protein translation. Messenger RNA regulatory elements typically reside within the 3' untranslated region (3'UTR) of the transcript and play a critical role in targeting specific mRNAs for posttranscriptional regulation through microRNA (miRNA) binding and adenylate- and uridylate-rich element RNA-binding proteins. In this review, we highlight the current advances in our understanding of the impact these RNA sequence elements have upon regulating PGE(2) levels. We also identify various RNA sequence elements consistently observed within the 3'UTRs of the genes involved in the PGE(2) pathway, indicating these binding sites for miRNAs and RNA-binding proteins to be central regulators of PGE(2) synthesis and function. These findings may provide a rationale for the development of new therapeutic approaches to control tumor growth and metastasis promoted by elevated PGE(2) levels.

The mRNA binding proteins HuR and tristetraprolin regulate cyclooxygenase 2 expression during colon carcinogenesis.

BACKGROUND & AIMS: During tumorigenesis, loss of rapid messenger RNA (mRNA) decay allows for overexpression of cancer-associated genes. The RNA-binding proteins Hu antigen R (HuR) and tristetraprolin (TTP) bind AU-rich elements in the 3' untranslated region of many cancer-associated mRNAs and target them for stabilization or rapid decay, respectively. We examined the functions of HuR and TTP during colon tumorigenesis and their ability to regulate cyclooxygenase (COX-2), a mediator of prostaglandin synthesis that increases in the colon tumor microenvironment. METHODS: We evaluated expression of HuR and TTP during colorectal tumorigenesis and in colon cancer cells and associated them with COX-2 expression. HuR and TTP-inducible cells were created to investigate HuR- and TTP-mediated regulation of COX-2. RESULTS: In normal colon tissues, low levels of nuclear HuR and higher levels of TTP were observed. By contrast, increased HuR expression and cytoplasmic localization were observed in 76% of adenomas and 94% of adenocarcinomas, and TTP expression was lost in >75% of adenomas and adenocarcinomas. Similar results were obtained for HuR and TTP mRNA levels in normal and staged tumor samples. In both adenomas and adenocarcinomas, COX-2 overexpression was associated with increased HuR and decreased TTP (P < .0001); similar associations were observed in colon cancer cells. HuR overexpression in cells up-regulated COX-2 expression, whereas overexpression of TTP inhibited it; limited TTP expression antagonized HuR-mediated COX-2 overexpression. CONCLUSIONS: Increased expression of the mRNA stability factor HuR and loss of the decay factor TTP occurs during early stages of colorectal tumorigenesis. These changes promote COX-2 overexpression and could contribute to colon tumorigenesis.

Mentoring new nurses in stressful times.

Meeting benchmarks of Ontario's Wait Time Strategy and the expansion of The Ottawa Hospital are key issues driving the recruitment of perioperative nurses in Ottawa and Eastern Ontario. Added pressures resulting from Canada's aging population and a nationwide nursing shortage mean perioperative nurses are overworked and understaffed. Preceptoring new members of staff raises valid concerns as many of the new recruits have little or no operating room experience. The Dreyfus Model of Skill Acquisition demonstrates the importance of time and patience in supporting the learning process. Mentoring is a valuable strategy in an effort to teach and guide new nurses, to increase nursing retention, and to promote professional growth and recognition. Building successful mentorship programs, through the creation of healthy organizational cultures, transformational leadership and staff development programs, will strengthen support for nurses in stressful times. The stress of meeting the province-wide benchmarks outlined in Ontario's Wait Time Strategy and the expansion of perioperative services at The Ottawa Hospital in Ontario are two key issues driving the need for the recruitment of nurses into the specialty of perioperative nursing. As a result of Canada's aging population and a nationwide nursing shortage, perioperative nurses are over-worked and under-staffed while being faced with the pressure to preceptor new staff members while struggling to meet the daily demands of the wait list strategy. This article discusses current trends in healthcare and the career path changes being made by many nurses in response to the demand for specialty trained nurses. It is followed by a brief explanation of the Dreyfus Model of Skill Acquisition. Mentoring is presented as an effective strategy in the guidance and teaching of new nurses with a discussion of the benefits and suggestions on how to build a successful mentorship program to support nurses in these stressful times.

Comparison of claims data on hospitalization rates and repeat procedures in patients receiving a bowel preparation prior to colonoscopy.

OBJECTIVES: To evaluate outcomes of colorectal screening using sodium picosulfate and magnesium citrate compared with other prescription bowel-preparation agents. Primary endpoints were rates of procedure-associated hospitalizations, diagnosis at hospitalization, and rates of early repeat screenings. METHODS: This retrospective cohort study identified patients using the Truven Health Analytics MarketScan databases, which contain fully adjudicated, de-identified, medical- and prescription-drug claims, as well as demographic and enrollment information for individuals with commercial, Medicaid, and Medicare supplemental insurance coverage. Patients who had a colonoscopy or sigmoidoscopy over a 3-year period were identified using International Classification of Diseases Clinical Modification procedure codes, recorded on claims from physicians and facilities. First, screening colonoscopy was identified for each patient, and the study was limited to those patients who could be observed for ≥6 months before and 3 months after the screening procedure. Total number of hospitalizations and rates of early repeat screenings were evaluated for all patients who received sodium picosulfate and magnesium citrate and compared with those who received other bowel-preparation agents. Individual prescription medications that could affect the outcome of the cleansing agent were identified; further evaluations were made to establish whether patients had comorbid conditions, such as chronic kidney disease, cardiovascular disease, or psychiatric illness. Statistical methods included descriptive statistics, two-tailed t-tests, and multivariate logistic regression. RESULTS: A total of 566,628 procedures were identified in the MarketScan databases and included in the study. Sodium picosulfate and magnesium citrate performed well in terms of safety outcomes, with no hospitalizations due to diagnosis of hyponatremia, dehydration, or other fluid disorders in the 10 days after procedure. Early repeat rates among sodium picosulfate and magnesium citrate patients were comparable with rates observed for all other cleansing agents. CONCLUSION: Outcomes of colorectal screening using sodium picosulfate and magnesium citrate were not significantly different compared with other prescription bowel-preparation agents.

The role of tristetraprolin in cancer and inflammation.

Messenger RNA decay is a critical mechanism to control the expression of many inflammation- and cancer-associated genes. These transcripts are targeted for rapid degradation through AU-rich element (ARE) motifs present in the mRNA 3' untranslated region (3'UTR). Tristetraprolin (TTP) is an RNA-binding protein that plays a significant role in regulating the expression of ARE-containing mRNAs. Through its ability to bind AREs and target the bound mRNA for rapid degradation, TTP can limit the expression of a number of critical genes frequently overexpressed in inflammation and cancer. Regulation of TTP occurs on multiple levels through cellular signaling events to control transcription, mRNA turnover, phosphorylation status, cellular localization, association with other proteins, and proteosomal degradation, all of which impact TTP's ability to promote ARE-mediated mRNA decay along with decay-independent functions of TTP. This review summarizes the current understanding of post-transcriptional regulation of ARE-containing gene expression by TTP and discusses its role in maintaining homeostasis and the pathological consequences of losing TTP expression.

The mRNA stability factor HuR inhibits microRNA-16 targeting of COX-2.

Commonly observed in colorectal cancer is the elevated expression of the prostaglandin (PG) synthase COX-2. In normal intestinal epithelium, the COX-2 mRNA is targeted for rapid decay through the 3'-untranslated region (3'-UTR) adenylate- and uridylate (AU)-rich element (ARE), whereas in tumors ARE-mediated decay is compromised. Here we show that the COX-2 ARE can mediate degradation through microRNA (miRNA)-mediated regulation. We identified miR-16 to bind the COX-2 3'-UTR and inhibit COX-2 expression by promoting rapid mRNA decay. In colorectal cancer cells and tumors, miR-16 levels were decreased approximately twofold and miR-16 expression in cancer cells attenuated COX-2 expression and PG synthesis. The COX-2 ARE is also bound by the RNA-binding protein HuR. In colorectal cancer tumors, HuR is overexpressed and localized within the cytoplasm, where it promotes ARE-mRNA stabilization. Under conditions of HuR overexpression, miR-16 was unable to promote rapid mRNA decay through the COX-2 ARE. Ribonucleoprotein immunoprecipitation of HuR showed direct association with miR-16 that was reversed when cytoplasmic trafficking of HuR was inhibited. Furthermore, this interaction between HuR and miR-16 promoted the downregulation of miR-16. These new results identify miR-16 as a central posttranscriptional regulator of COX-2 and show the ability of elevated levels of HuR to antagonize miR-16 function. Along with insight into altered ARE-mediated mRNA decay observed in colorectal cancer, these findings provide a new explanation for tumor-derived loss of miR-16.

Posttranscriptional Regulation of Cyclooxygenase 2 Expression in Colorectal Cancer.

Cyclooxygenase (COX)-2 enzyme catalyzes the rate-limiting step of prostaglandin formation in pathogenic states, and overexpression of COX-2 occurs at multiple stages of colon carcinogenesis, allowing elevated prostaglandin synthesis to occur in the tumor microenvironment. In normal cells, COX-2 expression levels are potently regulated at the posttranscriptional level through various RNA sequence elements present within the mRNA 3' untranslated region (3'UTR). A conserved AU-rich element functions to target COX-2 mRNA for rapid decay and translational inhibition through association with various RNA-binding proteins to influence the fate of COX-2 mRNA. The 3'UTR contains alternative polyadenylation signals that result in a shortened 3'UTR and loss of regulatory elements. Specific microRNAs have been identified to bind regions within the COX-2 3'UTR and control COX-2 expression. Recent evidence demonstrates the functional significance of the COX-2 3'UTR and how improper recognition of the 3'UTR can contribute to COX-2 overexpression in colorectal cancer.