Host knockout of E-prostanoid 2 receptors reduces tumor growth and causes major alterations of gene expression in prostaglandin E2-producing tumors

Abstract

Abstract. Prostaglandin E 2 (PGE 2 ) is elevated in a variety of malignant tumors and has been shown to affect several hallmarks of cancer. Accordingly, the PGE 2 receptor, E-prostanoid 2 (EP2), has been reported to be associated with patient survival and reduced tumor growth in EP2-knockout mice. Thus, the aim of the present study was to screen for major gene expression alterations in tumor tissue growing in EP2-knockout mice. EP2-knockout mice were bred and implanted with EP2 receptor-expressing and PGE 2 -producing epithelial-like tumors. Tumor tissue and plasma were collected and used for analyses with gene expression microarrays and multiplex enzyme-linked immunosorbent assays. Tumor growth, acute phase reactions/systemic inflammation and the expression of interleukin-6 were reduced in EP2-knockout tumor-bearing mice. Several hundreds of genes displayed major changes of expression in the tumor tissue when grown in EP2-knockout mice. Such gene alterations involved several different cellular functions, including stemness, migration and cell signaling. Besides gene expression, several long non-coding RNAs were downregulated in the tumors from the EP2-knockout mice. Overall, PGE 2 signaling via host EP2 receptors affected a large number of different genes involved in tumor progression based on signaling between host stroma and tumor cells, which caused reduced tumor growth.

Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review)

“…Prostaglandin E2 (PGE2) receptor 2 subtype (EP2) is a G protein-coupled plasma membrane receptor for PGE2, which acts through numerous signaling pathways to regulate various physiological functions, including tumor occurrence, invasion and metastasis, angiogenesis, chronic inflammation, tumor immunity and cell apoptosis (1). Recently, various studies have focused on identifying the specific EP2 receptors and signaling pathways that regulate the pleiotropic activities of the cyclooxygenase-2 (cOX-2)/PGE2/EP2 pathway (2)(3)(4)(5).…”

“…Over the past 10 years, cOX-2 and its prostaglandin products have attracted increasing attention due to their important roles in the progression of tumors of the lung, head and neck, prostate, colon, ovary, chest and liver (2,(6)(7)(8). However, inhibition of COX-2 using non-steroidal anti-inflammatory drugs (NSAIDs) and specific COX-2 inhibitors is associated with various side effects, including gastric ulcers and myocardial infarction (9), which have limited the use of these drugs (10).…”

Thymoquinone Suppresses Migration of Human Renal Carcinoma Caki-1 Cells through Inhibition of the PGE2-Mediated Activation of the EP2 Receptor Pathway

“…EP2 is mostly responsible for the protumorigenic effects of PGE 2 . EP2 knockout mice showed reduced tumorigenesis in a carcinogen-induced skin cancer model, while EP2 overexpressing transgenic mice exhibited increased numbers of tumors when compared with wild-type mice ( Sung et al ., 2006 ; Asting et al ., 2017 ). Moreover, the PGE 2 -EP2/EP4 signaling axis can induce MMP-9 expression as well as its activation, resulting in the invasion and migration of human endometrial epithelial and stromal cells ( Lee et al ., 2011 ).…”

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

“…Tumor growth is inhibited in EP2-knockout mice compared with wild-type mice 37-39 . Asting et al showed that tumor growth, systemic inflammation and the expression of interleukin-6 are reduced in www.nature.com/scientificreports www.nature.com/scientificreports/ EP2-knockout tumor-bearing mice 40 . Tian et al found that EP2 methylation is associated with a better prognosis of non-small cell lung cancer, and EP2 methylation is present with greater frequency in tumors with epidermal growth factor receptor (EGFR) mutation than in non-EGFR mutated tumors 41 .…”