Journal
INTERNATIONAL JOURNAL OF NANOMEDICINE
Volume 17, Issue -, Pages 1155-1170Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/IJN.S354314
Keywords
endometriosis; HOTAIR; exosomes; miR-761; HDAC1; STAT3; inflammation
Funding
- National Nature Science Foundation of China [82101724]
- Natural Science Foundation of Shandong Province, China [ZR2020MH243, ZR2020QH043]
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Exosomal HOTAIR promotes the progression and angiogenesis of endometriosis by regulating the miR-761/HDAC1 axis and activating STAT3-mediated inflammation, both in vitro and in vivo, providing a potential treatment for endometriosis.
Background: Long non-coding RNA (lncRNA) and exosomes are implicated in endometriosis development. We measured the expression of an exosomal lncRNA, homeobox transcript antisense RNA (HOTAIR), and explored its molecular mechanism in endometriosis progression. Methods: Expression of HOTAIR and microRNA (miR)-761 in different endometrial tissues was measured. Exosomes were isolated from a culture medium of endometrial stromal cells (ESCs). RT-qPCR was used to measure HOTAIR expression in different exosome types. CCK-8, Edu, wound healing, transwell assays, flow cytometry and tube formation were used to detect the role of exosomal HOTAIR on ESCs and human umbilical vein endothelial cells (HUVECs). The relationship among miR-761, HOTAIR, and histone deacetylase 1 (HDAC1) was verified by dual-luciferase reporter assay. ESCs were transfected with miR-761 mimics or HDAC1 small interfering RNA (si-RNA) to ascertain if alterations in expression of miR-761 or HDAC1 could reverse the effect of exosomal HOTAIR. Then, we detected the effect of the HOTAIR/miR-761/HDAC1 axis on signal transducer and activator of transcription 3 (STAT3)-mediated inflammation. In vivo experiments were conducted to verify in vitro results. Results: HOTAIR expression was upregulated and miR-761 expression was downregulated in ectopic endometrium tissues. HOTAIR was packaged into exosomes and transported from ESCs to surrounding cells. Exosomal HOTAIR promoted the proliferation, migration, and invasion, and inhibited the apoptosis of ESCs. Angiogenesis of HUVECs was enhanced after cultured with exosomal HOTAIR. HOTAIR acted as a competing endogenous RNA to downregulate miR-761 and increase HDAC1 expression. miR-761 overexpression or HDAC1 knockdown reversed the role of exosomal HOTAIR on ESCs and HUVECs. The HOTAIR/miR-761/ HDAC1 axis could activate STAT3-related proinflammatory cytokines and stattic (inhibitor of phosphorylated-STAT3) could reverse the effect of HOTAIR on ESCs and HUVECs. In vivo experiments suggested that exosomal HOTAIR promoted the growth of endometrial lesions in vivo. Conclusion: Exosomal HOTAIR promoted the progression and angiogenesis of endometriosis by regulating the miR-761/HDAC1 axis and activating STAT3-mediated inflammation in vitro and in vivo, which may provide promising treatment for endometriosis.
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