Considering the etiology of estrogen-mediated EC, the pathway of the 27HC remains a significant area of research. CYP7B1 is responsible for the metabolism of 27HC and its increased expression has been shown to predict a better prognosis in cancer 12–14. However, there is little research into the effect of CYP7B1 on the development and progression of EC. Therefore, it is important to evaluate whether CYP7B1 can be used as a prognostic indicator for patients with endometrial cancer.
In view of these invastigations, we formulated the hypothesis that CYP7B1 expression could countribute to the prognosis of patients with EC. Therefore, we have gathered new evidence regarding the expression of the enzyme required for breaking down 27HC, which is CYP7B1. CYP7B1 protein was detected in EC tissues, with notably higher levels in the cytoplasm compared to the nucleus. The expression level of CYP7B1 protein in PR-positiv tumors was higher than that in PR-negative tumors. Compared to PR-negative tumours, PR-positive tumours tended to have higher levels of CYP7B1 protein. These findings appear to parallel those reported for breast cancer where a higher proportion of PR-positive tumors were observed in CYP7B1-positive tumors compared to CYP7B1-negative tumors16. Furthermore, the present study showed that CYP7B1 protein expression decreased with age increasing, suggesting that accumulation of 27HC may occure in older patients. A significant positive correlation has been reported between the circulating levels of 27HC and cholesterol, and plasma 27HC levels have a tendency to rise with hypercholesterolemia and increasing age13,17,18. A breast cancer study also revealed that the elevation of 27HC in tumours was caused by a decrease in CYP7B1 expression13.
Given the role of CYP7B1 in 27HC metabolism, we hypothesised that CYP7B1 may influence the development of EC. The expression of the CY7B1 protein was confirmed in our study to be an independent predictor of OS, with higher OS observed in the high-CYP7B1 group compared to the low-CYP7B1 group. Consistent with our results, previous studies have shown that CYP7B1 mRNA expression was downregulated in endometrial cancer tissues compared to normal tissues, and its expression level was markedly lower in poorly differentiated than in moderately differentiated cancers8,19. ER regulates many physiological functions and plays a crucial role in the development of various types of tumours20–23. Absence of ER was significantly correlated with stage and grade of EC, while its high expression served as a predictor of better prognosis24–27. The current research discovered elevated levels of CYP7B1 protein in ER-positive tumors. The findings from subgroup analyses of ER-positive patients still supported a favorable association between high CYP7B1 protein expression and OS. Interestingly, CYP7B1 protein was more protective in patients aged ≥ 55 years compared to ER-positive patients aged < 55 years. Furthermore, the protective effect of CY7B1 protein was limited to postmenopausal ER-positive patients. The association between CYP7B1 and prognosis varied in different subgroups, which may be related to the levels of oestrogen. Estrogen levels decrease significantly and serum 27HC increases in postmenopausal women28,29. The promoter of CYP7B1 contains putative response elements for half palindromic hormone response elements (HREs) in the nucleotide sequence from − 738 to − 75811. Estrogen up-regulates CYP7B1, a target gene for estrogen-mediated regulation30,31. Estrogen has contrary effects on CYP7B1 due to ER status32. In the presence of ER, estradiol stimulates the catalytic activity and mRNA expression of CY7B1. Conversely, oestradiol inhibits CY7B1 activity when ER is absent. Tang et al. have explored the mechanism by which estrogen mediates the regulation of the CYP7B1 gene promoter31. However, CYP7B1 expression varies in different cancer tissues. In prostate cancer, local methylation of the CYP7B1 promoter leads to increased expression of the CYP7B1 gene33. In contrary, enhanced methylation of the CYP7B1 promoter in breast cancer cells downregulates its expression34. Further studies are therefore needed to clarify the precise mechanisms of CYP7B1 in EC.
Our research has some noteworthy limitations. Firstly, it is a retrospective study, and patients without available tumor tissue for CYP7B1 measurement would be excluded, potentially leading to selection bias. Secondly, the cohort of our study was relatively small and all patients were from a single hospital. Therefore, collecting more cases for a multicenter study could effectively diminish selection bias and potential confounding factors.