In recent years, there has been a growing interest in understanding the influence of modifiable risk factors on the development and progression of PCa and in particular regarding metabolic pathways that are involved in PCa aggressiveness 9. In our immunohistochemical analysis of malignant and benign prostate tissue, we revealed an increased expression of CYP7B1 in men with prostate cancer and an association between an increased risk of biochemical recurrence in a subgroup of men without diabetes.
Furthermore, CYP7B1 was associated with altered expression or activity of insulin receptors (IR-a and IR-b), along with potential involvement in pathways related to mRNA splicing (SRSF-1), fatty acid synthesis (FAS and ACC-1), ATPLy, CPT1a, SREBP, FAS and PSMA expression in prostate cancer.
Weihua et al. 11 showed that 5a-androstane-3b,17b-diol (3bAdiol) is an endogenous ER ligand. Cytochrome P450 (CYP) 7B1 and 3b-hydroxysteroid dehydrogenase (3b-HSD) are two enzymes that determine levels of 3bAdiol available in the ER and thus may influence control of prostate proliferation. CYP7B knockout mice show lower prostate proliferation rates compared to WT mice 12. Polymorphisms in the 3b-HSD gene are associated with prostate cancer risk 13. Jakobsson et al 14 screened the human CYP7B1 gene for possible polymorphisms. Only one single polymorphism was detected, a C–G change in the promoter –104 base pair from the transcription start site. The allele frequency was investigated in Swedish men and compared to a Korean population, and Authors found that that the frequency of the G-allele was 4.04% in Swedes but only 0.33% among Koreans. This polymorphism is associated with phenotypic differences in expression systems and vastly different allele frequencies in the two ethnic populations, resulting in large differences in prostate cancer incidence.
Studies conducted with CYP7B1-/- and ERb-/- knockout mice revealed that CYP7B1 is able to abolish ERb-mediated anti-proliferative effects via metabolism of the ERb ligand 5a- androstane-3b,17b-diol which is reported to counteract AR-mediated proliferation 12. Tang et al concluded that DHT is not only a precursor of 5a-androstane-3b,17b-diol, but may also control 5a-andro- stane-3b,17b-diol metabolism via effects on the CYP7B1 gene 15. These results suggest that androgens may be able to regulate estrogen levels within the prostate, a previously unknown relationship between androgens and estrogens within the prostate 15.
Lutz et al 16 showed a positive correlation of CYP7B1 expression with tumor content only in the samples in men with diabetes, while men without diabetes showed the opposite direction. CYP7B1 expression positively correlated with activity of androgen signaling and Ki-67 gene expression.
Therefore, downregulation of synthases or overexpression of degradative enzymes may cause a decrease in these protective steroids and a shift from estrogen to androgen signaling 17.
Interestingly, Kakiyama et al reported data showing that an inability to upregulate CYP7B1, in the setting of insulin resistance, results in the accumulation of toxic intracellular cholesterol metabolites that promote inflammation and hepatocyte injury 18. Authors provided strong evidence that insulin resistance-mediated dysregulation of CYP7B1 establishes a cellular mechanism for the accumulation of “toxic” intracellular cholesterol metabolites 18. These data showed that insulin resistance alters this pathway by leading to chronic lower expression of CYP7B1 18. As a result, the chronic accumulation of oxysterols appears not only to directly provide substrate for toxic metabolites but also to alter the regulation of pathways such as mitochondrial cholesterol uptake and FFA synthesis 19.
Although controversial, these data may justify the finding of our study that revealed in a subgroup analysis of patients without diabetes, a higher risk of biochemical recurrence among individuals with higher levels of CYP7B1 expression (HR = 1.78). In conclusion, a deeper understanding of the relationship between lipid metabolism and PCA progression is of great importance and should be explored in the near future to improve survival in PCA patients. Finally, we would like to mention some limitations. First, we were unable to examine the association between body weight composition and lipid expression. Second, we have not examined the link between metabolism and possible genomic alterations. Third, the short follow-up period in our cohort was virtually inadequate to assess overall survival. On the other hand, our study is one of the few studies that reported tissue changes in CYP7B1 metabolism in PCA and its association with progression and prognosis.