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BNC2 is a putative tumor suppressor gene in high-grade serous ovarian carcinoma and impacts cell survival after oxidative stress
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BNC2 is a putative tumor suppressor gene in high-grade serous ovarian carcinoma and impacts cell survival after oxidative stress
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Journal Article
BNC2 is a putative tumor suppressor gene in high-grade serous ovarian carcinoma and impacts cell survival after oxidative stress
2016
Overview
Rs3814113 is the single-nucleotide polymorphism (SNP) showing the strongest association with high-grade serous ovarian carcinoma (HGSOC) incidence and is located in an intergenic region about 44 kb downstream of basonuclin 2 (
BNC2
) gene. Lifetime number of ovulations is associated with increased risk to develop HGSOC, probably because of cell damage of extrauterine Müllerian epithelium by ovulation-induced oxidative stress. However, the impact of low-penetrance HGSOC risk alleles (e.g. rs3814113) on the damage induced by oxidative stress remains unclear. Therefore, the purpose of this study was to investigate whether rs3814113 genetic interval regulates
BNC2
expression and whether
BNC2
expression levels impact on cell survival after oxidative stress. To do this, we analyzed gene expression levels of
BNC2
first in HGSOC data sets and then in an isogenic cell line that we engineered to carry a 5 kb deletion around rs3814113. Finally, we silenced BNC2 and measured surviving cells after hydrogen peroxide (H
2
O
2
) treatment to simulate oxidative stress after ovulation. In this paper, we describe that
BNC2
expression levels are reduced in HGSOC samples compared with control samples, and that BNC2 expression levels decrease following oxidative stress and ovulation
in vitro
and
in vivo
, respectively. Moreover, deletion of 5 kb surrounding rs3814113 decreases
BNC2
expression levels in an isogenic cell line, and silencing of
BNC2
expression levels increases cell survival after H
2
O
2
treatment. Altogether, our findings suggest that the intergenic region located around rs3814113 regulates
BNC2
expression, which in turn affects cell survival after oxidative stress response. Indeed, HGSOC samples present lower
BNC2
expression levels that probably, in the initial phases of oncogenic transformation, conferred resistance to oxidative stress and ultimately reduced the clearance of cells with oxidative-induced damages.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ 13/44
/ 13/89
/ 38/22
/ 38/43
/ 38/61
/ 45/70
/ Animals
/ Cell Survival - drug effects
/ Cystadenocarcinoma, Serous - genetics
/ Cystadenocarcinoma, Serous - pathology
/ DNA-Binding Proteins - genetics
/ DNA-Binding Proteins - metabolism
/ Female
/ Gene Expression Regulation, Neoplastic - drug effects
/ Gene Silencing - drug effects
/ Genes
/ Humans
/ Hydrogen Peroxide - toxicity
/ Mice
/ Original
/ Ovarian Neoplasms - genetics
/ Ovarian Neoplasms - pathology
/ Ovaries
/ Polymorphism, Single Nucleotide - genetics
/ Single-nucleotide polymorphism
/ Tumors
