Cyclooxygenase-2 expression: Does it have a probable role in tumorigenesis mechanisms of renal cell carcinoma?

Sözen, Sinan; Gürocak, Serhat; Erdem, Özlem; Acar, Cenk; Kordan, Yakup; Akyol, Gülen; Alkibay, Turgut

doi:10.1007/s11255-007-9268-9

Cited by 11 publications

(10 citation statements)

References 25 publications

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“…Indeed, we were able to detect a similar connection between HuR and COX-2 expression in the RCC cell line, since HuR knockdown by siRNA led to the reduced expression of COX-2. The expression of COX-2 was shown to be associated with an advanced stage of RCC and other clinicopathological features such as tumour size and grade, but it is not an independent prognostic factor in RCC [15,[23][24][25]. Our results are in line with these previous results, as here COX-2 expression was associated with high nuclear grade and high clinical stage.…”

Section: Discussionsupporting

confidence: 90%

HuR expression is a marker of poor prognosis in renal cell carcinoma

et al. 2010

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The HuR protein is a nucleocytoplasmic protein which plays an important role in the regulation of mRNA stability, and dysregulation of its expression has been linked to carcinogenesis. We studied 152 patients with primary renal cell carcinoma (RCC) who underwent surgery for the removal of kidney tumours between 1990 and 1999. The mean follow-up was 90 months. The expression of HuR and cyclooxygenase-2 (COX-2) was determined by immunohistochemistry using monoclonal antibodies. The immunostaining results were associated with patient age, clinical stage, Fuhrman grade and patient outcome. Cytoplasmic expression of HuR and COX-2 was positive in 37 (25%) and 22 (15%) of the tumours, respectively. The expression of HuR was associated with stage. The expression of COX-2 was associated with stage and nuclear grade. The RCC-specific survival was reduced in patients whose tumours expressed HuR or COX-2. The hazard ratio (HR) of patients with HuR-expressing tumours was 2.18 (95% confidence interval (CI), 1.16-4.09; p = 0.015) and the HR of patients with COX-2-expressing tumours was 2.29 (95% CI, 1.15-4.54; p = 0.018). In the Cox regression analysis the only independent prognostic factor was stage (p < 0.001). Treatment of an RCC cell line (769-P) with HuR-targeted small interfering RNA resulted in the reduced expression of HuR and COX-2. We conclude that cytoplasmic HuR expression is associated with reduced RCC-specific survival. The HuR protein regulates the expression of COX-2 in RCC cells, which is one potential mechanism of action for the HuR-associated aggressive behaviour of RCC.

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Section: Discussionsupporting

confidence: 90%

HuR expression is a marker of poor prognosis in renal cell carcinoma

et al. 2010

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“…COX-2 expression has also been reported to correlate with cRCC prognosis. Although the precise relationship is not well-understood, most published studies report COX-2 expression to correlate with poor clinicopathologic features and predict a poor prognosis (Miyata et al , 2003; Tuna et al , 2004; Sozen et al , 2008; Li et al , 2009). One report, however, found that COX-2 expression predicted for a longer median overall survival (Kankuri-Tammilehto et al , 2010).…”

Section: Discussionmentioning

confidence: 99%

Cox-2 inhibition enhances the activity of sunitinib in human renal cell carcinoma xenografts

et al. 2013

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Background:Sunitinib (Su), a tyrosine kinase inhibitor of VEGFR, is effective at producing tumour response in clear cell renal cell carcinoma (cRCC), but resistance to therapy is inevitable. As COX-2 is a known mediator of tumour growth, we explored the potential benefit of COX-2 inhibition in combination with VEGFR inhibition in attempts at delaying tumour progression on Su.Methods:COX-2 expression was compared with areas of hypoxia in tumours that progressed on Su vs untreated tumours. Mice bearing human cRCC xenografts were treated with Su and the COX-2 inhibitor, celecoxib, and the effects on tumour growth were assessed. Sequential vs concurrent regimens were compared.Results:COX-2 expression was increased in cRCC xenografts in areas of tumour hypoxia. The combination of Su and celecoxib achieved longer times to tumour progression compared to treatment with either agent alone or to untreated control animals in four models. This effect was seen with concurrent but not with sequential therapy.Conclusion:COX-2 inhibition can extend the effectiveness of VEGFR inhibition. This effect is dependent on the timing of therapy. Clinical trials combining Su and COX-2 inhibitors should be considered as a means delaying time to progression on sunitinib in patients with metastatic cRCC.

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“…They inhibit tumor growth by inducing apoptosis of tumor cells and inhibiting the Wnt/␤-catenin signaling pathway [34]. In RCC, COX-2 expression is present in the majority of the tumors and correlates with worse stage, grade, and microvessel density and poorer survival [35][36][37][38].…”

Section: Discussionmentioning

confidence: 99%

Impact of Aspirin and Non-Aspirin Nonsteroidal Anti-Inflammatory Drugs on Outcomes in Patients with Metastatic Renal Cell Carcinoma

Hamieh

Moreira

Lin

et al. 2018

KCA

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Abstract.Background: Non-steroidal anti-inflammatory drugs (NSAIDs) have demonstrated an anti-tumorigenic effect in several cancers. However, their use is associated with an increased risk in renal cell carcinoma (RCC) and their effect has not been assessed in patients with metastatic disease. Objective: We investigated the impact of NSAIDs on survival outcomes in patients with metastatic RCC (mRCC). Methods: We conducted a pooled retrospective analysis of 4,736 mRCC patients treated on phase II and III clinical trials. Patients were categorized as: aspirin (ASA) only users, non-ASA NSAIDs only users, ASA and non-ASA NSAIDs users, and NSAIDs non-users. The primary endpoint was overall survival (OS). Progression free survival (PFS), overall response rate (ORR) and adverse events (AEs) were secondary endpoints. OS and PFS were estimated using the Kaplan-Meier method and were assessed using multivariate Cox regression analysis. Results: We identified 457 (10%) ASA only users, 639 (13%) non-ASA NSAIDs only users, 61 (1%) ASA and non-ASA NSAIDS users, and 3579 (76%) NSAIDs non-users. OS and PFS were significantly worse in non-ASA NSAIDs users compared to the NSAIDs non-users (OS hazard ratio (HR): 1.47, p < 0.0001, median 11.6 versus 21.1 months; PFS HR: 1.29, p < 0.0001, median 4.6 versus 7.4 months). There was no difference in survival in ASA users or ASA and non-ASA NSAIDs users compared to NSAIDs non-users. Conclusions: Our analysis demonstrates that NSAIDs do not confer a survival advantage in mRCC patients. Further studies are warranted to elucidate the interaction of NSAIDS with targeted therapy in mRCC.

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Cyclooxygenase-2 expression: Does it have a probable role in tumorigenesis mechanisms of renal cell carcinoma?

Cited by 11 publications

References 25 publications

HuR expression is a marker of poor prognosis in renal cell carcinoma

HuR expression is a marker of poor prognosis in renal cell carcinoma

Cox-2 inhibition enhances the activity of sunitinib in human renal cell carcinoma xenografts

Impact of Aspirin and Non-Aspirin Nonsteroidal Anti-Inflammatory Drugs on Outcomes in Patients with Metastatic Renal Cell Carcinoma

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