Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
J Pathol. 2018 Jun;245(2):147-152. doi: 10.1002/path.5069. Epub 2018 Apr 3.
Human papillomavirus (HPV) is required but not sufficient for cervical carcinoma (CxCa) development. Oestradiol (E ) promotes CxCa development in K14E7 transgenic mice expressing the HPV16 E7 oncoprotein under the control of the keratin (K14) promoter. E mainly functions through oestrogen receptor α (ERα). However, the role of ERα in human CxCa has been underappreciated largely because it is not expressed in carcinoma cells. We have shown that deletion of Esr1 (the ERα-coding gene) in the cervical stroma of K14E7 mice promotes regression of cervical intraepithelial neoplasia (CIN), the precursor lesion of CxCa. Here, we deleted Esr1 in the cervical epithelium but not in the stroma. We found that E induced cervical epithelial cell proliferation in epithelial ERα-deficient mice. We also found that E promoted the development of CIN and CxCa in epithelial ERα-deficient K14E7 mice and that all neoplastic epithelial cells were negative for ERα. In addition, proliferation indices were similar between ERα and ERα CxCa. These results indicate that epithelial ERα is not necessary for E -induced CIN and CxCa. Taking these findings together, we conclude that stromal ERα rather than epithelial ERα mediates oncogenic E signalling in CxCa. Our results support stromal ERα signalling as a therapeutic target for the disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
人乳头瘤病毒（HPV）是宫颈癌（CxCa）发展所必需的，但不是充分条件。雌二醇（E ）促进 K14E7 转基因小鼠的宫颈癌发展，这些小鼠在角蛋白（K14）启动子的控制下表达 HPV16 E7 癌蛋白。E 主要通过雌激素受体 α（ERα）发挥作用。然而，由于 ERα 在癌细胞中不表达，因此其在人类 CxCa 中的作用一直被低估。我们已经表明，在 K14E7 小鼠的宫颈基质中删除 Esr1（编码 ERα 的基因）可促进宫颈上皮内瘤变（CIN）的消退，这是 CxCa 的前病变。在这里，我们在宫颈上皮而不是基质中删除了 Esr1。我们发现 E 在上皮 ERα 缺失的小鼠中诱导宫颈上皮细胞增殖。我们还发现 E 在 ERα 缺失的上皮 K14E7 小鼠中促进 CIN 和 CxCa 的发展，并且所有肿瘤性上皮细胞均为 ERα 阴性。此外，ERα 和 ERα CxCa 之间的增殖指数相似。这些结果表明，上皮 ERα 对于 E 诱导的 CIN 和 CxCa 不是必需的。综合这些发现，我们得出结论，基质 ERα 而不是上皮 ERα 介导 CxCa 中的致癌 E 信号。我们的研究结果支持将基质 ERα 信号作为该疾病的治疗靶标。
版权所有 © 2018 英国和爱尔兰病理学学会。由 John Wiley & Sons，Ltd. 出版。
