Exosomal lncRNA HOTAIR Promotes the Progression and Angiogenesis of Endometriosis via the miR-761/HDAC1 Axis and Activation of STAT3-Mediated Inflammation

Abstract

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.

Histone Modifications and Non-Coding RNAs: Mutual Epigenetic Regulation and Role in Pathogenesis

“…In exosomes, it promotes proliferation, invasion, migration and inhibits the apoptosis of endometrial stromal cells. Acting as a competing endogenous RNA, it downregulates miR-761 and increase expression of its target gene HDAC1 [ 126 ]. It also plays an important role in EMT regulation in gastric cancer, switching the acetylation of H3K27 to methylation by the E cadherin promoter, which induces inhibition of E-cadherin transcription [ 61 ].…”

Recent progress of Bioinspired Hydrogel-based delivery system for endometrial repair

“…Frontiers in Bioengineering and Biotechnology frontiersin.org characteristic of hydrogel and the ability to controlled-release its embedded molecule, encapsulation of exosomes with hydrogel provide an outstanding candidate in plenty of treatments including bone and cartilage regeneration, cardiovascular diseases, spinal cord injury, periodontal and corneal repairs (Xie et al, 2022). Exosome has immense potential of treating injured endometrium by regulating EMT (Yao et al, 2019;Feng et al, 2020), miRNA (Tan et al, 2020;Shi et al, 2021), proliferation (Lv et al, 2020) and endometrium angiogenesis (Zhang et al, 2022). However, all these effects are achieved via the suboptimal approach of direct injection which restricts the activity of exosomes by local tissue irritation or reduced self-life.…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Potential Therapy for Diabetes Mellitus and Diabetic Complications

“…Compared with natural MSC-EVs, these engineered EVs show elevated abilities to promote blood vessel formation and reduce inflammation by weakening miR-383-induced VEGF downregulation [ 128 ]. HOX transcript antisense RNA (HOTAIR) has been reported to play critical roles in mediating the angiogenic effects of endothelial cells by enhancing VEGF expression and reversing miR-761-induced histone deacetylase 1 inhibition [ 129 , 130 ]. Born et al demonstrated that MSC treated with HOTAIR overexpression plasmids can produce EVs with increased HOTAIR content, which further accelerates angiogenesis and wound healing in db/db mice [ 131 ].…”