Cervical cancer (CC) is one of the most prevalent malignancies among females. Cytoprotective autophagy could confer cancer cell tolerance to hypoxic stress, promoting cell survival and adaptation. Aspartyl-tRNA synthetase 1 antisense 1 (DARS-AS1) is an oncogenic long non-coding RNA (lncRNA) in various cancers, but how DARS-AS1 regulates cytoprotective autophagy in hypoxic environment in CC remains unclear. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted to explore the interaction between hypoxia-inducible factor 1 subunit alpha (HIF1α) and DARS-AS1 promoter. Methylated RNA immunoprecipitation (MeRIP) followed by quantitative real-time polymerase-chain reaction (RT-qPCR) detected methylated RNA level. The process of autophagic maturation was monitored by immunofluorescence staining. Higher DARS-AS1 expression was found in CC tissues and cytoprotective. We also uncovered that hypoxic exposure induced cytoprotective autophagy via HIF1α/DARS-AS1/DARS axis. Moreover, DARS-AS1 was validated to facilitate DARS translation via recruiting N6-adenosine-methyltransferase methyltransferase like 3 (METTL3) and methyltransferase like 14 (METTL14), which bound with DARS mRNA DARS mRNA 5’ untranslated region (5ʹUTR) and promoting its translation. The present study demonstrated that the ‘HIF1α/DARS-AS1/DARS/ATG5/ATG3’ pathway regulated the hypoxia-induced cytoprotective autophagy of CC and might be a promising target of therapeutic strategies for patients afflicted with CC.
Background: The uterine endometrium is a tissue that needs sufficient energy to support its active physiological function, the damage of which is responsible for intrauterine adhesion. In this study, we investigated the evidence that mitochondrial transfer is involved in endometrial repair and explored the effects and possible mechanism of mitochondrial transfer.Methods: The study was approved by the regional ethics committee of Ningbo Women and Children’s Hospital (Date: 12/3/2021/No: EC2021-M004). Endometrial stromal cells were pretreated with hypoxia and cocultured with human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in vitro. Confocal imaging was used to assess mitochondrial transfer between the cells. The proliferation and ATP production of endometrial stromal cells were detected to evaluate the physiological function of the cells.Results: We found that coculture of hUCB-MSCs and endometrial stromal cells partially restored the proliferation and ATP production of hypoxic cells. Mitochondrial transfer was observed from hUCB-MSCs to hypoxic endometrial stromal cells. This process can be blocked by hUCB-MSCs pretreated with carbenoxolone disodium (CBX), which can block TNT connection formation.Conclusions: The mitochondria of stem cells could be transferred completely into hypoxic endometrial stromal cells, partially restoring the proliferation of injured cells in vitro. This process is proactive.Trial registration: The study was approved by the regional ethics committee of the Ningbo women and Children’s Hospital (Date: 12/3/2021/No: EC2021-M004).
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