Hormones and Cancer Lab, Department of Medical Sciences, Institute of Biomedicine, iBiMED, University of Aveiro, Aveiro, Portugal; Experimental Pathology and Therapeutics, Research Center, Portuguese Oncology Institute - Porto (IPO-Porto), Porto, Portugal.
Urology Department, Hospital Américo Boavida, Luanda, Angola; Center for the Study of Animal Science, CECA/ICETA, University of Porto, Porto, Portugal.
Urol Oncol. 2020 Sep;38(9):738.e23-738.e35. doi: 10.1016/j.urolonc.2020.04.022. Epub 2020 Jun 2.
Estrogen-like metabolites have been identified in S. haematobium, the helminth parasite that causes urogenital schistosomiasis (UGS) and in patients´ blood and urine during UGS. Estrogen receptor (ER) activation is enriched in the luminal molecular subtype bladder cancer (BlaCa). To date, the significance of ER to these diseases remains elusive. We evaluated ERα and ERβ expression in UGS-related BlaCa (n = 27), UGS-related non-malignant lesions (n = 35), and noninfected BlaCa (n = 80). We investigated the potential of ERα to recognize S. haematobium-derived metabolites by docking and molecular dynamics simulations and studied ERα modulation in vitro using 3 BlaCa cell lines, T24, 5637 and HT1376. ERα was expressed in tumor and stromal cells in approximately 20% noninfected cases and in 30% of UGS-related BlaCa, predominantly in the epithelial cells. Overall, ERα expression was associated with features of tumor aggressiveness such as high proliferation and p53 positive expression. ERα expression correlated with presence of schistosome eggs. ERβ was widely expressed in both cohorts but weaker in UGS-related cases. molecular dynamics simulations of the 4 most abundant S. haematobium-derived metabolites revealed that smaller metabolites have comparable affinity for the ERα active state than 17β-estradiol, while the larger metabolites present higher affinity. Our in vitro findings suggested that ERα activation promotes proliferation in ERα expressing BlaCa cells and that this can be reverted with anti-estrogenic therapy. In summary, we report differential ER expression between UGS-related BlaCa and noninfected BlaCa and provide evidence supporting a role of active ERα during UGS and UGS-induced carcinogenesis.
在引起尿路血吸虫病（UGS）的寄生虫旋毛形线虫（S. haematobium）以及 UGS 患者的血液和尿液中，已经鉴定出类雌激素代谢物。雌激素受体（ER）的激活在腔面分子亚型膀胱癌（BlaCa）中富集。迄今为止，ER 对这些疾病的意义仍不清楚。我们评估了 UGS 相关 BlaCa（n=27）、UGS 相关非恶性病变（n=35）和未感染 BlaCa（n=80）中 ERα 和 ERβ 的表达。我们通过对接和分子动力学模拟研究了 ERα 识别旋毛形线虫衍生代谢物的潜力，并使用 3 种 BlaCa 细胞系 T24、5637 和 HT1376 在体外研究了 ERα 的调节。ERα 在大约 20%的未感染病例和 30%的 UGS 相关 BlaCa 的肿瘤和基质细胞中表达，主要在上皮细胞中表达。总体而言，ERα 表达与肿瘤侵袭性特征相关，如高增殖和 p53 阳性表达。ERα 表达与血吸虫卵的存在相关。ERβ 在两个队列中均广泛表达，但在 UGS 相关病例中较弱。对 4 种最丰富的旋毛形线虫衍生代谢物的分子动力学模拟表明，较小的代谢物与 ERα 活性状态的亲和力与 17β-雌二醇相当，而较大的代谢物则具有更高的亲和力。我们的体外研究结果表明，ERα 激活促进 ERα 表达的 BlaCa 细胞增殖，而抗雌激素治疗可以逆转这种作用。总之，我们报告了 UGS 相关 BlaCa 与未感染 BlaCa 之间 ER 表达的差异，并提供了支持在 UGS 期间和 UGS 诱导的癌变过程中 ERα 活性的证据。
