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

Publisher: Impact Journals Country of Publication: United States NLM ID: 101532965 Publication Model: Print Cited Medium: Internet ISSN: 1949-2553 (Electronic) Linking ISSN: 19492553 NLM ISO Abbreviation: Oncotarget Subsets: MEDLINE

Original Publication: Albany, N.Y. : Impact Journals

Fallopian Tubes/*cytology ; Fallopian Tubes/*metabolism ; MicroRNAs/*metabolism ; Oxidative Stress/*genetics ; Reactive Oxygen Species/*metabolism; Animals ; Carcinogenesis ; Cell Differentiation/physiology ; Cell Proliferation/physiology ; Cellular Senescence/physiology ; Epithelial Cells/cytology ; Epithelial Cells/metabolism ; Female ; Heterografts ; Humans ; Mice ; Mice, Nude ; MicroRNAs/genetics ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism

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.

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P30 CA060553 United States CA NCI NIH HHS; R21 CA167038 United States CA NCI NIH HHS

Keywords: ROS-induced miRNA (ROSmiR); fallopian tube secretory cells; p53; senescence bypass; tumorigenesis

0 (MicroRNAs)
0 (Mirn182 microRNA, human)
0 (Reactive Oxygen Species)
0 (Tumor Suppressor Protein p53)

Date Created: 20151017 Date Completed: 20161213 Latest Revision: 20181113

20250114

PMC4770751

10.18632/oncotarget.5493

26472020