Liu Yugang, Qiang Wenan, Xu Xiaofei, Dong Ruifen, Karst Alison M, Liu Zhaojian, Kong Beihua, Drapkin Ronny I, Wei Jian-Jun
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Oncotarget. 2015 Nov 17;6(36):38983-98. doi: 10.18632/oncotarget.5493.
High grade serous ovarian carcinoma (HGSC) is a DNA instable tumor and its precursor is commonly found originating from the fimbriated end of the fallopian tube secretory epithelial (FTSE) cells. The local stresses via ovulation and related inflammation are risks for HGSC. In this study, we examined the cellular and molecular responses of FTSE cells to stress. We found that excess intracellular reactive oxygen species (ROS) in normal FTSE cells upregulated a subset of microRNA expression (defined as ROSmiRs). Most ROSmiRs' expression and function were influenced and regulated by p53, and together they drove the cells into stress-induced premature senescence (SIPS). However, ROS-induced miR-182 is regulated by β-catenin, not by p53. In normal FTSE cells, miR-182 overexpression triggers cellular senescence by p53-mediated upregulation of p21. Conversely, in cells with p53 mutations, miR-182 overexpression no longer enhances p21 but functions as an "Onco-miR". p53 dysfunction is a prerequisite for miR-182-mediated tumorigenesis. In addition, we found that human follicular fluid could significantly induce intracellular ROS in normal FTSE cells. These findings suggest that ROS and p53 mutations may trigger a series of events, beginning with overexpressing miR-182 by ROS and β-catenin, impairing the DNA damage response, promoting DNA instability, bypassing senescence and eventually leading to DNA instable tumors in FTSE cells.
高级别浆液性卵巢癌（HGSC）是一种DNA不稳定的肿瘤，其前体通常起源于输卵管分泌上皮（FTSE）细胞的伞端。排卵及相关炎症引起的局部应激是HGSC的危险因素。在本研究中，我们检测了FTSE细胞对应激的细胞和分子反应。我们发现，正常FTSE细胞内过量的活性氧（ROS）上调了一部分微小RNA的表达（定义为ROSmiRs）。大多数ROSmiRs的表达和功能受p53影响和调控，它们共同促使细胞进入应激诱导的早衰（SIPS）状态。然而，ROS诱导的miR-182受β-连环蛋白调控，而非p53。在正常FTSE细胞中，miR-182过表达通过p53介导的p21上调触发细胞衰老。相反，在p53突变的细胞中，miR-182过表达不再增强p21，而是发挥“致癌miR”的作用。p53功能障碍是miR-182介导肿瘤发生的前提条件。此外，我们发现人卵泡液可显著诱导正常FTSE细胞内的ROS。这些发现表明，ROS和p53突变可能引发一系列事件，首先是ROS和β-连环蛋白导致miR-182过表达，损害DNA损伤反应，促进DNA不稳定，绕过衰老，最终导致FTSE细胞发生DNA不稳定肿瘤。
