Prostaglandins induce early growth response 1 transcription factor mediated microsomal prostaglandin E2 synthase up-regulation for colorectal cancer progression

Abstract

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 E 2 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 PGF 2b . A PGF 2b 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 PGF 2b , 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.

FosB transcription factor regulates COX-2 expression in colorectal cancer cells without affecting PGE2 expression

“…Previous reports support the present finding that PGE2 content is not changed upon decreasing COX-2 expression (31)(32)(33)(34)(35). A number of authors have demonstrated that in the Vhl ∆IE /Apc min / + intestinal tumor model, the production of PGE2 is not dependent on the levels of COX-2, since despite the blockage of COX-2 activity by nimesulide, the PGE2 content remained elevated, suggesting that the high PGE2 levels observed were due to an increase in mPGES1 expression (31,32).…”

“…The high expression of COX-2 and mPGES1 in their studies was explained by the direct activation of the promoter region of these two genes by hypoxia-inducible factor 2α (31), which associates hypoxia with the COX-2/mPGES1/PGE2 axis. In other report, PGs were able to induce mPGES1 expression through the activation of early growth response 1, implying a positive regulatory feedback between these components (33). In addition, mPGES1 has been observed to be increased in CRC tumor tissues and to correlate with a worse prognosis (34).…”

Prostaglandin F2α-induced TGFβ-PMEPA1 pathway is a critical mediator of epithelial plasticity and ovarian carcinoma progression

“…In this regard, higher COX2 expression and PG levels have been detected in different tumors, which could explain the NSAIDs beneficial effects in cancer prevention and treatment (3). Prostaglandin F2 (PGF2) has been scarcely studied on cancer although it has been detected in several tumor types and cancer patient body fluids (4,5) and only recently has been mechanistically associated with cancer progression (6). PGF2 is produced through the combined action of cyclooxygenases (COX) and different isomerases, AKR1B1 and AKR1C3 among others, with scarce reports implicating them in cancer (7).…”

“…Increased contents of prostaglandins in ovarian tumors have been described in previous studies, possibly regulating cell proliferation and apoptosis in this specific tumor context (11), being PGE2 the most extensively studied in this context (10). However, we have found another PG with an emerging role in colon cancer progression (6) with a close relationship with the female reproductive system (14). PMEPA1 (also known as TMEPA1, transmembrane prostate androgen induced 1) gene was first identified as a highly androgen-inducible gene with abundant expression in prostatic epithelial cells, which eventually was described as a direct transcriptional target of the androgen receptor (AR) (15) but also being upregulated in renal cell carcinoma (16).…”

“…β-catenin also binds with the intracellular domain of epithelial-cadherin (E-Cadherin) to form a complex which subsequently connects to the actin cytoskeleton, mediates intercellular adhesion, and regulates tumor cell invasion and metastasis (28). 6 Several oncogenic pathways (i.e., Wnt/β-catenin) increase cell plasticity (29). TGF-β is a potent regulator of cell plasticity through the induction of epithelial to mesenchymal transition (EMT) (30), directly activating the expression of transcription factors such as SNAI1/2, Twist and ZEB1/2, which are the key regulators of the EMT program.…”