Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, 18100 Granada, Spain.
Excellence Research Unit "Modeling Nature" (MNat), University of Granada, 18016 Granada, Spain.
Int J Mol Sci. 2023 Jan 7;24(2):1221. doi: 10.3390/ijms24021221.
In general, the risk of being diagnosed with cancer increases with age; however, the development of estrogen-receptor-positive (ER+) cancer types in women are more closely related to menopausal status than age. In fact, the general risk factors for cancer development, such as obesity-induced inflammation, show differences in their association with ER+ cancer risk in pre- and postmenopausal women. Here, we tested the role of the principal estrogens in the bloodstream before and after menopause, estradiol (E2) and estrone (E1), respectively, on inflammation, epithelial-to-mesenchymal transition (EMT) and cancer stem cell enrichment in the human ER+ cervical cancer cell line HeLa. Our results demonstrate that E1, contrary to E2, is pro-inflammatory, increases embryonic stem-transcription factors (ES-TFs) expression and induces EMT in ER+ HeLa cells. Moreover, we observed that high intratumoural expression levels of 17β-Hydroxysteroid dehydrogenase (HSD17B) isoforms involved in E1 synthesis is a poor prognosis factor, while overexpression of E2-synthetizing HSD17B isoforms is associated with a better outcome, for patients diagnosed with ER+ ovarian and uterine corpus carcinomas. This work demonstrates that E1 and E2 have different biological functions in ER+ gynaecologic cancers. These results open a new line of research in the study of ER+ cancer subtypes, highlighting the potential key oncogenic role of E1 and HSD17B E1-synthesizing enzymes in the development and progression of these diseases.
一般来说，癌症的诊断风险会随着年龄的增长而增加；然而，女性中雌激素受体阳性（ER+）癌症类型的发展与绝经状态的关系比年龄更为密切。事实上，癌症发展的一般风险因素，如肥胖引起的炎症，在绝经前和绝经后妇女的 ER+癌症风险中，其关联存在差异。在这里，我们分别测试了绝经前后血液中主要雌激素，即雌二醇（E2）和雌酮（E1），对人 ER+宫颈癌细胞系 HeLa 中炎症、上皮间质转化（EMT）和癌症干细胞富集的作用。我们的结果表明，与 E2 相反，E1 具有促炎作用，增加胚胎干细胞转录因子（ES-TFs）的表达，并诱导 ER+HeLa 细胞发生 EMT。此外，我们观察到，参与 E1 合成的 17β-羟类固醇脱氢酶（HSD17B）同工型在肿瘤内的高表达水平是预后不良的因素，而 E2 合成酶 HSD17B 同工型的过表达与 ER+卵巢和子宫体癌患者的更好结局相关。这项工作表明，E1 和 E2 在 ER+妇科癌症中有不同的生物学功能。这些结果为研究 ER+癌症亚型开辟了新的研究方向，强调了 E1 和 HSD17B E1 合成酶在这些疾病发展和进展中的潜在关键致癌作用。
