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

Abstract

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...

The Interaction of Human Papillomavirus Infection and Prostaglandin E2 Signaling in Carcinogenesis: A Focus on Cervical Cancer Therapeutics

“…PTGER2 expression increases while PTGER3 expression decreases during cervical neoplasia development [ 118 , 123 ], suggesting these receptors might be considered as positive and negative prognostic markers of cervical cancer lesions, respectively. PTGER2 expression is a prognostic factor for the overall survival in the subgroup of negative PTGER3, and high galectin-3 expressed cervical cancer patients [ 124 ]. PTGER3 signaling promotes the migration of cervical cancer cells through the modulation of the urokinase-type plasminogen activator receptor [ 125 ].…”

Unraveling the Molecular Nexus between GPCRs, ERS, and EMT

“…In another example, prostaglandin receptor EP2 (Class A, lipid receptor family) activation was shown to protect against ER stress-induced apoptosis via cAMP-mediated downregulation of p53 and its target gene PUMA [ 72 ]. Elevated EP2 signaling is associated with breast cancer [ 73 ], cervical cancer [ 74 ], and bladder cancer [ 75 ]. High expression of AGTR1 is also associated with metastasis of multiple cancer types and is negatively correlated with the prognosis of ovarian cancer.…”

<p>GRK2 Suppresses Hepatocellular Carcinoma Metastasis and Invasion Through Down-Regulation of Prostaglandin E Receptor 2</p>

“…10 EP2 has proven to be beneficial to stimulate tumor vascular endothelial cell growth, promote tumor cell invasion and metastasis in the development of various tumors. 11,12 In addition, our previous studies found that butaprost, a selective EP2 receptor agonist, can significantly stimulate the proliferation and invasion of HCC cells. 13 However, whether the precise mechanism of GRK2 involving in HCC is related with EP2 receptor remain to be elucidated.…”