Cyclooxygenase-2 Is an Independent Prognostic Factor in Gastric Cancer and Its Expression Is Regulated by the Messenger RNA Stability Factor HuR

Mrena, Johanna; Wiksten, Jan-Patrik; Thiel, Alexandra; Kokkola, Arto; Pohjola, Leena; Lundin, Johan; Nordling, Stig; Ristimäki, Ari; Haglund, Caj

doi:10.1158/1078-0432.ccr-05-0764

Cited by 136 publications

(116 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Consistent with this idea, HuR expression was altered in cytomegalovirus-infected cells resulting in a compromised antiviral activity (44), and aberrant regulation of HuR was detected in HPV18-associated cervical neoplasia (45). Altered expression of HuR and HuR target mRNAs has also been reported in cancers of the breast (46), gut (47), ovary (48), and colon (26). These studies suggest a role for dysregulated HuR expression in the etiologies of human viral infections and malignancies; however, the importance of RNase-L, as compared with other HuR targets, in these pathologies remains to be determined.…”

Section: ј-Utr-mediated Regulation In the Biologicalmentioning

confidence: 67%

Post-transcriptional Regulation of RNase-L Expression Is Mediated by the 3′-Untranslated Region of Its mRNA

Li¹,

Andersen²,

Ezelle³

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

RNase-L mediates critical cellular functions including antiviral, pro-apoptotic, and tumor suppressive activities; accordingly, its expression must be tightly regulated. Little is known about the control of RNASEL expression; therefore, we examined the potential regulatory role of a conserved 3-untranslated region (3-UTR) in its mRNA. The 3-UTR mediated a potent decrease in the stability of RNase-L mRNA, and of a chimeric ␤-globin-3-UTR reporter mRNA. AU-rich elements (AREs) are cis-acting regulatory regions that modulate mRNA stability. Eight AREs were identified in the RNase-L 3-UTR, and deletion analysis identified positive and negative regulatory regions associated with distinct AREs. In particular, AREs 7 and 8 served a strong positive regulatory function. HuR is an ARE-binding protein that stabilizes ARE-containing mRNAs, and a predicted HuR binding site was identified in the region comprising AREs 7 and 8. Co-transfection of HuR and RNase-L enhanced RNase-L expression and mRNA stability in a manner that was dependent on this 3-UTR region. Immunoprecipitation demonstrated that RNase-L mRNA associates with a HuR containing complex in intact cells. Activation of endogenous HuR by cell stress, or during myoblast differentiation, increased RNase-L expression, suggesting that RNase-L mRNA is a physiologic target for HuR. HuR-dependent regulation of RNase-L enhanced its antiviral activity demonstrating the functional significance of this regulation. These findings identify a novel mechanism of RNase-L regulation mediated by its 3-UTR.The control of mRNA stability is a potent regulatory mechanism, as small changes in mRNA half-life result in dramatic changes in the mRNA available for translation into functional protein. Such post-transcriptional regulation provides a means to rapidly alter gene expression in response to diverse stimuli, and is frequently observed in genes encoding proteins with essential cellular functions such as proliferation and stress response. One of the most extensively studied RNA decay pathways involves AU-rich elements (AREs) 2 present in the 3Ј-untranslated region (3Ј-UTR) of mRNAs (1). The AUUUA sequence is a loose consensus that is found in many but not all AREs; the absence of a strict sequence motif likely reflects the importance of structural components in ARE function (2). The influence of AREs on mRNA turnover occurs through an interaction with ARE-binding proteins (AREBPs) that can function to destabilize or stabilize target mRNAs by modulating access to the decay machinery. Specifically, AREs modulate deadenylation, and decapping, two critical steps in mRNA decay (3, 4); consistent with a link between mRNA stability and translation, some AREBPs function to regulate translation (5, 6). Several AREBPs have been identified, and genetic manipulation of specific AREBPs in mice, such as HuR and tristetraprolin, resulted in dramatic and complex phenotypes that are associated with inflammation and stress response (7,8). These phenotypes underscore the critical role of AREBPs in gene re...

show abstract

Section: ј-Utr-mediated Regulation In the Biologicalmentioning

confidence: 67%

Post-transcriptional Regulation of RNase-L Expression Is Mediated by the 3′-Untranslated Region of Its mRNA

Li¹,

Andersen²,

Ezelle³

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Cox-2 is overexpressed in several malignant tumors and the increase in expression may due to dysregulation of mRNA stability (10)(11)(12). Recently, a correlation between the protein expression level of HuR and Cox-2 was found in colon, breast, stomach, ovary and uterine cervical cancer cells (9,(13)(14)(15)(16). There have been no reports on the relationship between HuR and Cox-2 expression in colorectal cancer tumors from patients in South Korea.…”

Section: Resultsmentioning

confidence: 99%

Cytoplasmic Expression of HuR is Related to Cyclooxygenase-2 Expression in Colon Cancer

et al. 2009

View full text Add to dashboard Cite

“…According to our previous data, 198 of 309 (64%) of the specimens had positive cytoplasmic HuR immunoreactivity, and 273 (88%) had nuclear positivity. 16 Cytoplasmic HuR immunoreactivity associated with cyclin A, (p < 0.001, v 2 5 12.0) (Table II), but nuclear did not (p 1.0).…”

Section: Associations Of Cyclin a With Clinicopathological Factors Anmentioning

confidence: 91%

“…Previously, expression of HuR has been associated with the poor prognosis of breast, 14 ovarian 15 and gastric cancers. 16 The prognostic role of cyclin A in gastric cancer is unclear. In this study, we evaluated the association of cyclin A expression with clinicopathological parameters and survival in patients with gastric adenocarcinomas.…”

mentioning

confidence: 99%

Prognostic significance of cyclin A in gastric cancer

Mrena

Wiksten

Kokkola

et al. 2006

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

High level of cyclin A promotes carcinogenesis, and overexpression of cyclin A has been associated with poor prognosis of cancer patients. We validated the prognostic role of cyclin A in gastric cancer and evaluated its correlation with expression of an mRNA stability factor HuR. From 342 consecutive histologically confirmed gastric cancer patients were obtained 325 representative tissue specimens for cyclin A and 316 for HuR immunohistochemistry. Specimens were stained by cyclin A and HuR specific monoclonal antibodies. Nuclear immunostaining detected in 5% of the tumor cells was considered the cut-off for cyclin A positivity. Positive HuR immunoreactivity was scored as nuclear or cytoplasmic. Associations between scores, clinicopathological factors and survival were calculated by the v 2 -test, Fisher's exact test, Kaplan-Meier test and Cox model. Cyclin A detected in the nuclei of cancer cells was positive in 55% (179 of 325) of the specimens; 40% (127 of 316) of the specimens had cytoplasmic and 88% (279 of 316) nuclear immunoreactivity of HuR. Cyclin A expression was an independent prognostic factor for poor survival. Cyclin A immunoreactivity was associated with old age, high stage, proximal location of the tumor, intestinal type, noncurative resection, advanced penetration depth and with nodal metastases but not distant metastases. Furthermore, cyclin A expression was associated with cytoplasmic HuR expression, whereas no association with nuclear HuR was evident. Cyclin A is an independent prognostic factor in gastric cancer, and one mechanism for its overexpression may depend on cytoplasmic localization of HuR. ' 2006 Wiley-Liss, Inc.Key words: cyclin A; HuR; gastric cancer; prognosis; survival Cyclin A belongs to the cyclin protein superfamily, and it can activate two different cyclin-dependent kinases, CDK1 and CDK2. The level of cyclin A accumulates progressively throughout the interphase and disappears rapidly at the end of mitosis. Currently, phosphorylated cyclin A-CDK complex is suggested to play an important role in the initiation of DNA replication in the S phase. The precise function of cyclin A in mitosis is unclear, but it may prevent other cyclins from degradation. Overexpression of cyclin A and dysregulation of CDK-cyclin complexes promote tumor cell growth, which can be facilitated by phosphorylation of oncoproteins and tumor suppressors. 1,2 In gastric cancer, cell-cycle regulators have been connected with poor prognosis. For example, overexpression of cyclin E, which also binds to CDK2 and controls the G1-S transition, has been associated with aggressive disease. 3,4 Furthermore, strongly positive cyclin E in the tumors of patients having surgery with intent to cure is a marker of poor prognosis, and concurrent expression of cyclin E and p53 is an independent prognostic factor. 5 However, there are also reports indicating that cyclin E expression does not correlate with clinicopathological parameters, 6 or is associated with good prognosis. 7 Overexpression of cyclin A correlates with po...

show abstract

Cyclooxygenase-2 Is an Independent Prognostic Factor in Gastric Cancer and Its Expression Is Regulated by the Messenger RNA Stability Factor HuR

Cited by 136 publications

References 35 publications

Post-transcriptional Regulation of RNase-L Expression Is Mediated by the 3′-Untranslated Region of Its mRNA

Post-transcriptional Regulation of RNase-L Expression Is Mediated by the 3′-Untranslated Region of Its mRNA

Cytoplasmic Expression of HuR is Related to Cyclooxygenase-2 Expression in Colon Cancer

Prognostic significance of cyclin A in gastric cancer

Contact Info

Product

Resources

About