MiR-210-3p protects endometriotic cells from oxidative stress-induced cell cycle arrest by targeting BARD1

Abstract

Endometriosis is associated with benign but adversely developed cysts in the extrauterine environment. The oxidative imbalanced environment induces DNA damage and affects cell cycle progression of endometrial stromal cells (ESCs) and endometrial epithelial cells, but how endometriotic cells maintain proliferation in the presence of oxidative stress is not clear. Growing evidence has indicated that the ectopic hypoxic microenvironment and oxidative stress can stimulate the growth of endometriotic cells, which is mainly due to the increase of HIF-1α. We found that the master hypoxia-associated miRNA miR-210-3p was increased in stromal and glandular cells of ectopic lesions compared with that of eutopic and normal endometria and was consistent with the expression of HIF-1α and the local oxidative stress-induced DNA damage predictor 8-OHdG. Moreover, miR-210-3p was upregulated in ESCs and Ishikawa cells under hypoxic conditions but not in normoxic culture. Knockdown of miR-210-3p induced a G2/M arrest of ESCs and Ishikawa cells under hypoxia, while no effect was found under normoxia. BARD1 was identified as a target of miR-210-3p. BARD1 expression was decreased in endometriotic tissues compared with eutopic and normal endometria and negatively correlated with the expression of miR-210-3p. Multivariate regression analysis showed that BARD1 downregulation could serve as an indicator for endometriotic severity. Our results suggest that miR-210-3p attenuates the G2/M cell cycle checkpoint by inactivating BRCA1 complex function in response to DNA damage under hypoxia via targeting the 3′ untranslated region of BARD1 mRNA. Endometriotic mouse model experiments showed that intraperitoneal injection of the miR-210-3p inhibitor or vitamin C suppressed the growth of endometriotic lesions. Together, our results demonstrate that endometriotic cells inhibit BARD1/BRCA1 function by upregulating miR-210-3p, which might be the underlying mechanism for endometriotic cell maintenance of growth in oxidative stress. Furthermore, inhibition of miR-210-3p and administration of vitamin C are promising approaches for the treatment of endometriosis.

Integrated Analysis of miRNA-mRNA Interaction Network in Porcine Granulosa Cells Undergoing Oxidative Stress

“…Additionally, in another ongoing study, we showed that miR-130a significantly induces porcine GC apoptosis and follicular atresia by targeting the TGF- β signaling pathway (data not shown). Moreover, several DEmiRNAs, such as miR-141 and miR-210, have been proven to control oxidative stress responses in ovarian cancer cells and endometriotic cells by targeting p38α and BARD1 , respectively [67, 68], suggesting that several identified DEmiRNAs may function as modulators in response to oxidative stress. We also identified 19 novel, function-unknown DEmiRNAs which require further investigation.…”

A Narrative Review of the Role of Diet and Lifestyle Factors in the Development and Prevention of Endometrial Cancer

“…Secondly, extended longevity, resulting in a higher median age for women, results in a promulgation of these effects such that DNA or oxidative damage and other DNA/RNA/ miRNA mutational events accumulate in affected cells and so create the focus for endometrial hyperplasia that is a precursor for the early stage development of EC [ 87 , 88 ]. This early stage EC (type 1, grade 1) is particularly difficult to detect, as such patients are often asymptomatic.…”

Hypoxia‑induced lactate dehydrogenase A protects cells from apoptosis in endometriosis

“…Hypoxia inducible factor (HIF)-1α is a key regulator of hypoxia, which makes it a useful marker of cellular hypoxic stress. Our previous studies revealed that HIF-1α expression was increased in ectopic lesions compared with that in eutopic tissues and normal endometrium (7,8). Ectopic endometrial cells may ultimately use the hypoxic microenvironment to promote cell adhesion, proliferation and angiogenesis (5,6); however, how ectopic cells convert the metabolism to overcome and adapt to hypoxic microenvironments before new vasculature forms in ectopic lesions is not clear.…”