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

Asting,Annika Gustafsson; Iresjö,Britt‑Marie; Nilsberth,Camilla; Smedh,Ulrika; Lundholm,Kent

doi:10.3892/ol.2016.5448

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

Authors:
- Annika Gustafsson Asting
- Britt‑Marie Iresjö
- Camilla Nilsberth
- Ulrika Smedh
- Kent Lundholm
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Affiliations: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE‑413 45 Gothenburg, Sweden, Department of Geriatric Medicine, Linköping University, SE-581 85 Linköping, Sweden
Published online on: November 30, 2016 https://doi.org/10.3892/ol.2016.5448
Pages: 476-482

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Abstract

Prostaglandin E2 (PGE2) is elevated in a variety of malignant tumors and has been shown to affect several hallmarks of cancer. Accordingly, the PGE2 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 PGE2‑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, PGE2 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.

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1	Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP and Meade TW: Effect of daily aspirin on long-term risk of death due to cancer: Analysis of individual patient data from randomised trials. Lancet. 377:31–41. 2011. View Article : Google Scholar : PubMed/NCBI
2	Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP and Meade TW: Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 376:1741–1750. 2010. View Article : Google Scholar : PubMed/NCBI
3	Greenhough A, Smartt HJ, Moore AE, Roberts HR, Williams AC, Paraskeva C and Kaidi A: The COX-2/PGE2 pathway: Key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis. 30:377–386. 2009. View Article : Google Scholar : PubMed/NCBI
4	Wang D and Dubois RN: Eicosanoids and cancer. Nat Rev Cancer. 10:181–193. 2010. View Article : Google Scholar : PubMed/NCBI
5	Gustafsson A, Hansson E, Kressner U, Nordgren S, Andersson M, Wang W, Lönnroth C and Lundholm K: EP1-4 subtype, COX and PPAR gamma receptor expression in colorectal cancer in prediction of disease-specific mortality. Int J Cancer. 121:232–240. 2007. View Article : Google Scholar : PubMed/NCBI
6	Gustafsson A, Hansson E, Kressner U, Nordgren S, Andersson M, Lönnroth C and Lundholm K: Prostanoid receptor expression in colorectal cancer related to tumor stage, differentiation and progression. Acta Oncol. 46:1107–1112. 2007. View Article : Google Scholar : PubMed/NCBI
7	Sonoshita M, Takaku K, Sasaki N, Sugimoto Y, Ushikubi F, Narumiya S, Oshima M and Taketo MM: Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc(Delta 716) knockout mice. Nat Med. 7:1048–1051. 2001. View Article : Google Scholar : PubMed/NCBI
8	Seno H, Oshima M, Ishikawa TO, Oshima H, Takaku K, Chiba T, Narumiya S and Taketo MM: Cyclooxygenase 2- and prostaglandin E(2) receptor EP(2)-dependent angiogenesis in Apc (Delta716) mouse intestinal polyps. Cancer Res. 62:506–511. 2002.PubMed/NCBI
9	Keith RL, Geraci MW, Nana-Sinkam SP, Breyer RM, Hudish TM, Meyer AM, Malkinson AM and Dwyer-Nield LD: Prostaglandin E2 receptor subtype 2 (EP2) null mice are protected against murine lung tumorigenesis. Anticancer Res. 26:2857–2861. 2006.PubMed/NCBI
10	Iresjö BM, Wang W, Nilsberth C, Andersson M, Lönnroth C and Smedh U: Food intake, tumor growth, and weight loss in EP2 receptor subtype knockout mice bearing PGE2-producing tumors. Physiol Rep. 3:e124412015. View Article : Google Scholar : PubMed/NCBI
11	Ma X, Aoki T, Tsuruyama T and Narumiya S: Definition of prostaglandin E2-EP2 signals in the colon tumor microenvironment that amplify inflammation and tumor growth. Cancer Res. 75:2822–2832. 2015. View Article : Google Scholar : PubMed/NCBI
12	Tilley SL, Audoly LP, Hicks EH, Kim HS, Flannery PJ, Coffman TM and Koller BH: Reproductive failure and reduced blood pressure in mice lacking the EP2 prostaglandin E2 receptor. J Clin Invest. 103:1539–1545. 1999. View Article : Google Scholar : PubMed/NCBI
13	Andersson C, Gelin J, Iresjö BM and Lundholm K: Acute-phase proteins in response to tumor growth. J Surg Res. 55:607–614. 1993. View Article : Google Scholar : PubMed/NCBI
14	Gelin JL, Moldawer LL, Iresjö BM and Lundholm KG: The role of the adrenals in the acute phase response to interleukin-1 and tumor necrosis factor-alpha. J Surg Res. 54:70–78. 1993. View Article : Google Scholar : PubMed/NCBI
15	Lundholm K, Gelin J, Hyltander A, Lönnroth C, Sandström R, Svaninger G, Körner U, Gülich M, Kärrefors I, Norli B, et al: Anti-inflammatory treatment may prolong survival in undernourished patients with metastatic solid tumors. Cancer Res. 54:5602–5606. 1994.PubMed/NCBI
16	Lönnroth C, Andersson M, Asting AG, Nordgren S and Lundholm K: Preoperative low dose NSAID treatment influences the genes for stemness, growth, invasion and metastasis in colorectal cancer. Int J Oncol. 45:2208–2220. 2014.PubMed/NCBI
17	Ganesh T: Prostanoid receptor EP2 as a therapeutic target. J Med Chem. 57:4454–4465. 2014. View Article : Google Scholar : PubMed/NCBI
18	Mutoh M, Watanabe K, Kitamura T, Shoji Y, Takahashi M, Kawamori T, Tani K, Kobayashi M, Maruyama T, Kobayashi K, et al: Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis. Cancer Res. 62:28–32. 2002.PubMed/NCBI
19	Brouxhon S, Konger RL, VanBuskirk J, Sheu TJ, Ryan J, Erdle B, Almudevar A, Breyer RM, Scott G and Pentland AP: Deletion of prostaglandin E2 EP2 receptor protects against ultraviolet-induced carcinogenesis, but increases tumor aggressiveness. J Invest Dermatol. 127:439–446. 2007. View Article : Google Scholar : PubMed/NCBI
20	Sung YM, He G and Fischer SM: Lack of expression of the EP2 but not EP3 receptor for prostaglandin E2 results in suppression of skin tumor development. Cancer Res. 65:9304–9311. 2005. View Article : Google Scholar : PubMed/NCBI
21	Ansari KM, Sung YM, He G and Fischer SM: Prostaglandin receptor EP2 is responsible for cyclooxygenase-2 induction by prostaglandin E2 in mouse skin. Carcinogenesis. 28:2063–2068. 2007. View Article : Google Scholar : PubMed/NCBI
22	Kamiyama M, Pozzi A, Yang L, DeBusk LM, Breyer RM and Lin PC: EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival. Oncogene. 25:7019–7028. 2006. View Article : Google Scholar : PubMed/NCBI
23	Li HJ, Reinhardt F, Herschman HR and Weinberg RA: Cancer-stimulated mesenchymal stem cells create a carcinoma stem cell niche via prostaglandin E2 signaling. Cancer Discov. 2:840–855. 2012. View Article : Google Scholar : PubMed/NCBI
24	Li YJ, Kanaji N, Wang XQ, Sato T, Nakanishi M, Kim M, Michalski J, Nelson AJ, Farid M, Basma H, et al: Prostaglandin E switches from a stimulator to an inhibitor of cell migration after epithelial-to-mesenchymal transition. Prostaglandins Other Lipid Mediat 116–117. 1–9. 2015. View Article : Google Scholar
25	Pino MS, Nawrocki ST, Cognetti F, Abruzzese JL, Xiong HQ and McConkey DJ: Prostaglandin E2 drives cyclooxygenase-2 expression via cyclic AMP response element activation in human pancreatic cancer cells. Cancer Biol Ther. 4:1263–1269. 2005. View Article : Google Scholar : PubMed/NCBI
26	Brouxhon S, Kyrkanides S, O'Banion MK, Johnson R, Pearce DA, Centola GM, Miller JN, McGrath KH, Erdle B, Scott G, et al: Sequential down-regulation of E-cadherin with squamous cell carcinoma progression: Loss of E-cadherin via a prostaglandin E2-EP2 dependent posttranslational mechanism. Cancer Res. 67:7654–7664. 2007. View Article : Google Scholar : PubMed/NCBI
27	Díaz-Muñoz MD, Osma-García IC, Fresno M and Iniguez MA: Involvement of PGE2 and the cAMP signalling pathway in the up-regulation of COX-2 and mPGES-1 expression in LPS-activated macrophages. Biochem J. 443:451–461. 2012. View Article : Google Scholar : PubMed/NCBI
28	Liou JY, Ellent DP, Lee S, Goldsby J, Ko BS, Matijevic N, Huang JC and Wu KK: Cyclooxygenase-2-derived prostaglandin e2 protects mouse embryonic stem cells from apoptosis. Stem Cells. 25:1096–1103. 2007. View Article : Google Scholar : PubMed/NCBI
29	Niho N, Kitamura T, Takahashi M, Mutoh M, Sato H, Matsuura M, Sugimura T and Wakabayashi K: Suppression of azoxymethane-induced colon cancer development in rats by a cyclooxygenase-1 selective inhibitor, mofezolac. Cancer Sci. 97:1011–1014. 2006. View Article : Google Scholar : PubMed/NCBI
30	Kitamura T, Itoh M, Noda T, Matsuura M and Wakabayashi K: Combined effects of cyclooxygenase-1 and cyclooxygenase-2 selective inhibitors on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice. Int J Cancer. 109:576–580. 2004. View Article : Google Scholar : PubMed/NCBI
31	Fernández-Martínez AB and Lucio-Cazaña J: Intracellular EP2 prostanoid receptor promotes cancer-related phenotypes in PC3 cells. Cell Mol Life Sci. 72:3355–3373. 2015. View Article : Google Scholar : PubMed/NCBI
32	Sato T, Konomi K, Fujii R, Aono H, Aratani S, Yagishita N, Araya N, Yudoh K, Beppu M, Yamano Y, et al: Prostaglandin EP2 receptor signalling inhibits the expression of matrix metalloproteinase 13 in human osteoarthritic chondrocytes. Ann Rheum Dis. 70:221–226. 2011. View Article : Google Scholar : PubMed/NCBI
33	Rinn JL and Chang HY: Genome regulation by long noncoding RNAs. Annu Rev Biochem. 81:145–166. 2012. View Article : Google Scholar : PubMed/NCBI
34	Brosius J: Waste not, want not-transcript excess in multicellular eukaryotes. Trends Genet. 21:287–288. 2005. View Article : Google Scholar : PubMed/NCBI
35	Pollard KS, Salama SR, King B, Kern AD, Dreszer T, Katzman S, Siepel A, Pedersen JS, Bejerano G, Baertsch R, et al: Forces shaping the fastest evolving regions in the human genome. PLoS Genet. 2:e1682006. View Article : Google Scholar : PubMed/NCBI
36	Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, et al: Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci USA. 110:3507–3512. 2013. View Article : Google Scholar : PubMed/NCBI
37	Bastien L, Sawyer N, Grygorczyk R, Metters KM and Adam M: Cloning, functional expression, and characterization of the human prostaglandin E2 receptor EP2 subtype. J Biol Chem. 269:11873–11877. 1994.PubMed/NCBI