Prostaglandins induce early growth response 1 transcription factor mediated microsomal prostaglandin E2 synthase up-regulation for colorectal cancer progression.
Cyclooxygenase2 (COX2) has been associated with cell growth, invasiveness, tumor progression and metastasis of colorectal carcinomas. However, the downstream prostaglandin (PG)-PG receptor pathway involved in these effects is poorly characterized.We studied the PG-pathway in gene expression databases and we found that PTGS2 (prostaglandin G/H synthase and cyclooxygenase) and PTGES (prostaglandin E synthase) are co-expressed in human colorectal tumors. Moreover, we detected that COX2 and microsomal Prostaglandin E2 synthase 1 (mPGES1) proteins are both up-regulated in colorectal human tumor biopsies.Using colon carcinoma cell cultures we found that COX2 overexpression significantly increased mPGES1 mRNA and protein. This up-regulation was due to an increase in early growth response 1 (EGR1) levels and its transcriptional activity. EGR1 was induced by COX2-generated PGF2α. A PGF2α receptor antagonist, or EGR1 silencing, inhibited the mPGES1 induction by COX2 overexpression. Moreover, using immunodeficient mice, we also demonstrated that both COX2- and mPGES1-overexpressing carcinoma cells were more efficient forming tumors.Our results describe for the first time the molecular pathway correlating PTGS2 and PTGES in colon cancer progression. We demonstrated that in this pathway mPGES1 is induced by COX2 overexpression, via autocrine PGs release, likely PGF2α, through an EGR1-dependent mechanism. This signaling provides a molecular explanation to PTGS2 and PTGES association and contribute to colon cancer advance, pointing out novel potential therapeutic targets in this oncological context.
Centro de Biología Molecular ''Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Universidad Autónoma de Madrid, Madrid, Spain.|Instituto Sanitario Princesa de Investigacion Sanitaria (IIS-P), Madrid, Spain.
Konstantinos
K
Stamatakis
Centro de Biología Molecular ''Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Universidad Autónoma de Madrid, Madrid, Spain.
Marta
M
Jimenez-Martinez
Centro de Biología Molecular ''Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Universidad Autónoma de Madrid, Madrid, Spain.
Alba
A
Jimenez-Segovia
Centro de Biología Molecular ''Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Universidad Autónoma de Madrid, Madrid, Spain.
Isabel
I
Chico-Calero
Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Carretera de Colmenar, Madrid, Spain.
Elisa
E
Conde
Centro de Biología Molecular ''Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Universidad Autónoma de Madrid, Madrid, Spain.
Javier
J
Galán-Martínez
Centro de Biología Molecular ''Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Universidad Autónoma de Madrid, Madrid, Spain.
Julia
J
Ruiz
Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Carretera de Colmenar, Madrid, Spain.
Alejandro
A
Pascual
Centro de Biología Molecular ''Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Universidad Autónoma de Madrid, Madrid, Spain.
Beatriz
B
Barrocal
Centro de Biología Molecular ''Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Universidad Autónoma de Madrid, Madrid, Spain.
Ricardo
R
López-Pérez
Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Carretera de Colmenar, Madrid, Spain.
María Laura
ML
García-Bermejo
Centro de Biología Molecular ''Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Universidad Autónoma de Madrid, Madrid, Spain.|Instituto Sanitario Princesa de Investigacion Sanitaria (IIS-P), Madrid, Spain.
Manuel
M
Fresno
D000818:Animals; D015153:Blotting, Western; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D018613:Microscopy, Confocal; D008861:Microsomes / Q000201:enzymology; D000071876:Prostaglandin-E Synthases; D011453:Prostaglandins / Q000378:metabolism*; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D015854:Up-Regulation
C094815:NAB1 protein, human; D011453:Prostaglandins; D012097:Repressor Proteins; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse
colorectal adenocarcinoma; cyclooxygenase 2; early growth response 1; microsomal prostaglandin E2 synthase