In this study, we examined PTGER2 (prostaglandin E receptor 2, EP2) expression in colorectal cancer, in relation to expression of prostaglandin-endoperoxide synthase 2 (PTGS2, the HUGO Gene Nomenclature Committee-approved official symbol for cycloxygenase-2, or COX-2), microsatellite instability (MSI), the CpG island methylator phenotype (CIMP) and clinical outcome. PTGER2 is a G-protein-coupled receptor that mediates the action of prostaglandin E2 (PGE2), a major product of PTGS2 (COX-2), which contributes to colon cancer development. As the inverse association of PTGS2 (COX-2) with MSI and CIMP has been reported in colorectal cancer (32
), a better understanding of interrelationship between PTGER2, PTGS2 (COX-2), MSI and CIMP may shed lights on biological mechanisms of PTGS2 (COX-2)-induced tumorigenesis. We found that PTGER2 overexpression was significantly associated with MSI-high, independent of CIMP status and other variables. Our data further support PTGER2 expression as one of unique characteristics of MSI-high colorectal cancer.
Our resource of a large number of colorectal cancers derived from the two prospective cohort studies has enabled us to precisely estimate the frequency of colorectal cancers with a specific molecular feature (such as PTGER2 overexpression, MSI-high, CIMP-high, etc.) at the population level. The large number of cases has also provided a sufficient power in our multivariate logistic regression analysis and survival analysis.
Studying molecular changes is important in colorectal cancer research (53
). A molecular classification based on MSI and CIMP status is increasingly important, because MSI and CIMP reflect global genomic and epigenomic aberrations, respectively, in tumor cells (30
). Some studies including our previous study indicated the “inverse” association of PTGS2 (COX-2) expression with MSI-high and CIMP-high in colorectal cancer (32
). Interestingly, our current study has shown that PTGER2 overexpression is positively associated with MSI-high, independent of CIMP status. MSI status reflects genomic aberrations in tumor cells and determines molecular characteristics and phenotypes of colorectal cancer. Our findings suggest that PTGER2 overexpression may play a role in the pathway to MSI-high cancer, whereas PTGS2 (COX-2) overexpression may be important in the pathway to MSI-low/MSS cancer (). Additional studies are necessary to confirm our findings as well as to elucidate the exact relationship between the PTGS2 (COX-2)/PTGER2 pathway and MSI status in colorectal tumorigenesis.
The prognostic role of PTGER2 overexpression in human cancer is inconclusive. A study on esophageal squamous cell carcinoma (N=226) has reported that PTGER2 overexpression is related with poor prognosis in univariate analysis, but not in multivariate analysis (62
). Another study on lung cancer has indicated the prognostic value of PTGER2 overexpression among individuals with squamous cell carcinoma (N=39), but not among those with adenocarcinoma (N=43) (63
). In a previous study on colorectal cancer (N=72) (64
), PTGER2 overexpression was independently associated with poor prognosis. However, most of these studies were limited by low statistical power. Small studies (N<100) with null results have much higher likelihood of being unpublished than small studies with “significant” results, leading to publication bias. In our current study (N=516), PTGER2 overexpression was not significantly associated with clinical outcome, while it was highly significantly associated with MSI-high (P<0.0001). An experimental study using colon cancer cells has shown that PTGER2 expression leads to increased tumor growth, supporting PTGER2 as an oncogene (24
). Nonetheless, colorectal cancers with activation of a given oncogene or inactivation of a given tumor suppressor are not always associated with poor clinical outcome. For example, MSI-high cancers are associated with inactivation of many tumor suppressors and with good prognosis (65
). Our findings suggest that PTGER2 overexpression may not mark an aggressive type of colorectal cancer.
The PTGS2 (COX-2)/PGE2 pathway is increasingly important as a target for colorectal cancer treatment and chemoprevention (10
). Within our two prospective cohort studies, regular aspirin use reduced the risk of developing colorectal cancer, in particular, tumor with PTGS2 (COX-2) overexpression (8
). In addition, regular aspirin use after the diagnosis of colorectal cancer was associated with lower risk of colorectal cancer-specific and overall mortality, especially among patients with tumors with PTGS2 (COX-2) overexpression (9
). Thus, in the near future, PTGS2 (COX-2) expression may well serve as a selective marker for aspirin treatment in the management of colorectal cancer (16
). Aspirin has been reported to suppress MSI in mismatch repair-deficient and hereditary nonpolyposis colorectal cancer cells (66
). Considering the intriguing relation between PTGS2 (COX-2), PTGER2, and MSI status demonstrated in our current study, the effect of aspirin on colorectal cancer may be influenced not only by PTGS2 (COX-2) expression status but also PTGER2 expression status. In this respect, our findings may be of clinical interest. We currently plan further analysis on PTGER2 expression, aspirin use and patient survival to test this latter hypothesis.
In conclusion, PTGER2 overexpression in colorectal cancer is associated with MSI, independent of CIMP status, PTGS2 (COX-2), and other variables. An exact mechanism of the possible pathogenic link between the PTGS2 (COX-2)/PTGER2 pathway and MSI needs to be investigated. A better understanding of the role of PTGER2 in colorectal cancer is important for the purpose of cancer therapy and chemoprevention targeting the PTGS2 (COX-2) pathway.