Role of miR-182 in response to oxidative stress in the cell fate of human fallopian tube epithelial cells

Yugang Liu, Wenan Qiang, Xiaofei Xu, Ruifen Dong, Alison M. Karst, Zhaojian Liu, Beihua Kong, Ronny I. Drapkin, Jian Jun Wei*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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 ß-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 ß-catenin, impairing the DNA damage response, promoting DNA instability, bypassing senescence and eventually leading to DNA instable tumors in FTSE cells.

Original languageEnglish (US)
Pages (from-to)38983-38998
Number of pages16
JournalOncotarget
Volume6
Issue number36
DOIs
StatePublished - 2015

Keywords

  • Fallopian tube secretory cells
  • ROS-induced miRNA (ROSmiR)
  • Senescence bypass
  • Tumorigenesis
  • p53

ASJC Scopus subject areas

  • Oncology

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