The Prostaglandin EP3 Receptor Is an Independent Negative Prognostic Factor for Cervical Cancer Patients

Heidegger, H; Dietlmeier, Sebastian; Ye, Yao; Kühn, Christina; Vattai, Aurelia; Aberl, Caroline Anna; Jeschke, Udo; Mahner, Sven; Kost, Bernd

doi:10.3390/ijms18071571

Cited by 22 publications

(27 citation statements)

References 28 publications

(34 reference statements)

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“…Another study observed that upregulation of EP3 expression in prostate cancer cells is associated with preventive and anticancer effects 45 . We observed that the prostaglandin EP3 receptor was an independent negative prognostic factor for cervical cancer 11 . www.nature.com/scientificreports www.nature.com/scientificreports/ Previous studies found a correlation between galectin-3 and the development of cervical cancer.…”

Section: Discussionmentioning

confidence: 69%

“…For this combined analysis we used the whole number of patients enrolled in our study (n = 250), no pre-selection was done. Our previous study demonstrated that high EP3 expression was associated with a poor overall survival rate of the same patients 11 . In the subgroup of cervical cancer patients with no EP3 expression www.nature.com/scientificreports www.nature.com/scientificreports/ (IRS score = 0, n = 45/250, 18%), the survival rate differed in the high-EP2 (n = 29/45, 64%) ( Fig.…”

Section: Resultsmentioning

confidence: 90%

“…The percentage of EP2 expression is significantly decreased from FIGO I to FIGO II. We applied the same cervical cancer tissues as were used in our previously published studies 11 . EP2 was stained in the cytoplasm of 94.8% cervical cancer tissues (235/248), consisting of 188 cases with squamous cell carcinoma and 47 cased with AC.…”

Section: Resultsmentioning

confidence: 99%

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The prostaglandin receptor EP2 determines prognosis in EP3-negative and galectin-3-high cervical cancer cases

Dietlmeier

Yao

Kühn

et al. 2020

Sci Rep

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Recently our study identified EP3 receptor and galectin-3 as prognosticators of cervical cancer. The aim of the present study was the analysis of EP2 as a novel marker and its association to EP3, galectin-3, clinical pathological parameters and the overall survival rate of cervical cancer patients. Cervical cancer tissues (n = 250), as also used in our previous study, were stained with anti-EP2 antibodies employing a standardized immunohistochemistry protocol. Staining results were analyzed by the iRS scores and evaluated for its association with clinical-pathological parameters. H-test of EP2 percent-score showed significantly different expression in FIGO I-IV stages and tumor stages. Kaplan-Meier survival analyses indicated that EP3-negative/EP2-high staining patients (EP2 IRS score ≥2) had a significantly higher survival rate than the EP3-negative/EP2-low staining cases (p = 0.049). In the subgroup of high galectin-3 expressing patients, the group with high EP2 levels (IRS ≥2) had significantly better survival rates compared to EP2-low expressing group (IRS <2, p = 0.044). We demonstrated that the EP2 receptor is a prognostic factor for the overall survival in the subgroup of negative EP3 and high galectin-3 expressed cervical cancer patients. EP2 in combination with EP3 or galectin-3 might act as prognostic indicators of cervical cancer. EP2, EP3, and galectin-3 could be targeted for clinical diagnosis or endocrine treatment in cervical cancer patients, which demands future investigations.Cervical cancer is the fourth most common female cancer type worldwide with nearly half a million new cases annually. 83% of all cases occur in developing countries, whereas in developed countries only 3.6% of new cancer cases are cervical cancer 1 . One of the main risk factors for cervical cancer is a persistent infection with specific Human Papillomavirus (HPV), the high-risk papillomavirus (HR-HPV) 2 . HPV is manifested in nearly 99.7% of all cervical cancer patients 3 . Belonging to the papillomavirus family, HPV is a non-enveloped, small, double-stranded DNA virus 3-5 . More than 200 HPV genotypes have been characterized worldwide 6 . The sub-classification in high-risk and low-risk is important for the HPV infections of the genital tract 5 . Low-risk subtypes, such as HPV-6, HPV-11, HPV-26, HPV-40, HPV-42, are the cause of genital warts and non-malignant lesions 2,5 , whereas high-risk HPV types like HPV-16 and HPV-18 were identified in cervical and other anogenital cancers 2,5 .Tumor cell differentiation, apoptosis, and oncogenesis are associated with prostanoids, including prostaglandin E 2 (PGE 2 ), prostaglandin D 2 (PGD 2 ), prostaglandin I 2 (PGI 2 ), prostaglandin F 2 (PGF 2 ) and thromboxane A 2 7 . Prostaglandins are important for tumor progression and tumor-associated angiogenesis as Amano et al. described 8 . PGE 2 signaling is well-known for apoptosis inhibition, angiogenesis, metastatic formation, and tumor progression. The membrane-bound EP receptors specific for PGE 2 are G-protein coupled receptors and...

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Section: Discussionmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 90%

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The prostaglandin receptor EP2 determines prognosis in EP3-negative and galectin-3-high cervical cancer cases

Dietlmeier

Yao

Kühn

et al. 2020

Sci Rep

Self Cite

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“…Substrate-staining was performed for two and a half minutes with DAB (chromogen substrate kit, Dako, Hamburg, Germany). Counterstain by hemalaun colouring and dehydrogenation in an ascending alcohol series followed, before the slides were mounted with "Eukitt" (Orsatec, Bobingen, Germany) (Heidegger et al 2017). According to information in the human protein atlas sigma and placenta tissue were chosen as positive control.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Heidegger et al previously indicated that the prostaglandin E2-receptor EP3 is an independent negative prognostic factor in cervical cancer patients. The expression levels and the clinical outcome were proven to correlate with tumour stage (Heidegger et al 2017). In addition, Hester et al demonstrated that EP3 receptor expression levels correlate inversely with grades of CIN (Hester et al 2019).…”

Section: Introductionmentioning

confidence: 99%

The role of EP-2 receptor expression in cervical intraepithelial neoplasia

Schmoeckel

Fraungruber

Kühn

et al. 2020

Histochem Cell Biol

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Prostaglandin induced signalling is involved in different cancers. As previously described, the EP3 receptor expression decreases with increasing stage of cervical intraepithelial lesions (CIN). In addition, in cervical cancer EP3 is an independent prognosticator for overall survival and correlates with FIGO stages. Currently the role of Prostaglandin 2 receptor 2 (EP2) in CIN is unknown. The aim of this study was to analyse the expression of EP2 for potential prognostic value for patients with cervical dysplasia. EP2 expression was analysed by immunohistochemistry in 33 patient samples (CIN1-3) using the immune-reactivity scoring system (IRS). Expression levels were correlated with clinical outcome to analyse prognostic relevance in patients with CIN2. Data analysis was performed using non parametric Kruskal-Wallis and Spearman rank sum test. Cytoplasmic expression levels of EP2 correlated significantly (p < 0.001) with different grades of cervical dysplasia. Median EP2-IRS in CIN1 was 2 (n = 8), 3 in CIN2 (n = 9) and 6 in CIN3 (n = 16). Comparing regressive (n = 3, median IRS = 2) to progressive (n = 6, median IRS = 4) CIN2 cases the median IRS differed significantly (p = 0.017). Staining intensity (p = 0.009) and IRS (p = 0.005) of EP2 and EP3 correlate inversely. EP2 expression level significantly increases with higher grade of CIN and could qualify as a potential prognostic marker for the regressive or progressive course in CIN2 lesions. These findings emphasize the significant role of PGE2 signalling in CIN and could help to identify targets for future therapies.

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COX-2-PGE2-EPs in gynecological cancers

Yao

Wang

Jeschke

et al. 2020

Arch Gynecol Obstet

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Purpose Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (COXibs) inhibit the progression of endometrial cancer, ovarian cancer and cervical cancer. However, concerning the adverse effects of NSAIDs and COXibs, it is still urgent and necessary to explore novel and specific anti-inflammation targets for potential chemoprevention. The signaling of cyclooxygenase 2-prostaglandin E 2-prostaglandin E 2 receptors (COX-2-PGE 2-EPs) is the central inflammatory pathway involved in the gynecological carcinogenesis. Methods Literature searches were performed to the function of COX-2-PGE 2-EPs in gynecological malignancies. Results This review provides an overview of the current knowledge of COX-2-PGE 2-EPs signaling in endometrial cancer, ovarian cancer and cervical cancer. Many studies demonstrated the upregulated expression of the whole signaling pathway in gynecological malignancies and some focused on the function of COX-2 and cAMP-linked EP2/EP4 and EP3 signaling pathway in gynecological cancer. By contrast, roles of EP1 and the exact pathological mechanisms have not been completely clarified. The studies concerning EP receptors in gynecological cancers highlight the potential advantage of combining COX enzyme inhibitors with EP receptor antagonists as therapeutic agents in gynecological cancers. Conclusion EPs represent promising anti-inflammation biomarkers for gynecological cancer and may be novel treatment targets in the near future.

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The Prostaglandin EP3 Receptor Is an Independent Negative Prognostic Factor for Cervical Cancer Patients

Cited by 22 publications

References 28 publications

The prostaglandin receptor EP2 determines prognosis in EP3-negative and galectin-3-high cervical cancer cases

The prostaglandin receptor EP2 determines prognosis in EP3-negative and galectin-3-high cervical cancer cases

The role of EP-2 receptor expression in cervical intraepithelial neoplasia

COX-2-PGE2-EPs in gynecological cancers

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