Abstract
Endometriosis is a common gynecological disease characterized by diminished apoptosis, sustained ectopic survival of dysfunctional endometrial cells. Hypoxia has been implicated as a crucial microenvironmental factor that contributes to endometriosis. It has been reported that long non‐coding RNA MALAT1 (lncRNA‐MALAT1) highly expressed in endometriosis and up‐regulated by hypoxia. Hypoxia may also induce autophagy, which might act as cell protective mechanism. However, the relationship between lncRNA‐MALAT1 and autophagy under hypoxia conditions in endometriosis remains unknown. In the present study, we found that both lncRNA‐MALAT1 and autophagy level were up‐regulated in ectopic endometrium from patients with endometriosis, and its expression level correlates positively with that of hypoxia‐inducible factor‐1α (HIF‐1α). In cultured human endometrial stromal cells, both lncRNA‐MALAT1 and autophagy were induced by hypoxia in a time‐dependent manner and lncRNA‐MALAT1 up‐regulation was dependent on HIF‐1α signalling. Our analyses also show that knockdown of lncRNA‐MALAT1 suppressed hypoxia induced autophagy. Furthermore, inhibiting autophagy with specific inhibitor 3‐Methyladenine (3‐MA) and Beclin1 siRNA enhanced apoptosis of human endometrial stromal cells under hypoxia condition. Collectively, our findings identify that lncRNA‐MALAT1 mediates hypoxia‐induced pro‐survival autophagy of endometrial stromal cells in endometriosis.
Highlights
Endometriosis is a common, complex benign gynecological disorder, defined as the extra‐uterine growth of endometrial tissues.[1]
To the best of our knowledge, this is the first report on the effects of LncRNA‐MALAT1 on autophagy which was induced by hypoxia in human endometrial stromal cells
We found that the expression of Long non‐coding RNAs (lncRNAs)‐MALAT1 was remarkably up‐regulated and positively correlated with the expression of hypoxia‐ inducible factor‐1α (HIF‐1α) and autophagy marker light chain 3 (LC3) in ovarian endometriosis tissue samples
Summary
Endometriosis is a common, complex benign gynecological disorder, defined as the extra‐uterine growth of endometrial tissues.[1]. The mechanism underlying the reduced endometrial cell apoptosis in endometriosis remain largely unknown. Previous studies reported that hypoxia may play a role in the survival and angiogenesis of retrograde endometrial cells in implanted ectopic endometriotic lesions.[9]. During this process HIF‐1α regulate the expression of multiple target genes involved in different processes including angiogenesis, apoptosis, and autophagy.[10,11]. Despite the expansion of our knowledge about autophagy, the mechanisms responsible for the aberrant activation of autophagy and the detailed effect of autophagy on survival of human endometrial cells under the hypoxia condition remain largely unknown in the context of endometriosis. Considering the fact that the elevated expression of lncRNA‐MALAT1 in ovarian endometriosis and its connection with autophagy as well as the up‐regulation of both lncRNA‐MALAT1 and autophagy were up‐ regulated by hypoxia, we have been suggested that up‐regulation of lncRNA‐MALAT1 by hypoxia may promote autophagy which acts as a cell pro‐survival mechanism in endometriosis
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