Endometriosis is a benign gynaecological disease which shares some
characteristics with malignancy like migration and invasion. It has been
reported that both Hypoxia-Inducible Factor-1α (HIF-1α) and
autophagy were upregulated in ectopic endometrium of patients with ovarian
endometriosis. However, the crosstalk between HIF-1α and autophagy in
the pathogenesis of endometriosis remains to be clarified. Accordingly, we
investigated whether autophagy was regulated by HIF-1α, as well as
whether the effect of HIF-1α on cell migration and invasion is mediated
through autophagy upregulation. Here, we found that ectopic endometrium from
patients with endometriosis highly expressed HIF-1α and autophagy
related protein LC3. In cultured human endometrial stromal cells (HESCs),
autophagy was induced by hypoxia in a time dependent manner and autophagy
activation was dependent on HIF-1α. In addition, migration and invasion
ability of HESCs were enhanced by hypoxia treatment, whereas knockdown of
HIF-1α attenuated this effect. Furthermore, inhibiting autophagy with
specific inhibitors and Beclin1 siRNA attenuated hypoxia triggered migration and
invasion of HESCs. Taken together, these results suggest that HIF-1α
promotes HESCs invasion and metastasis by upregulating autophagy. Thus autophagy
may be involved in the pathogenesis of endometriosis and inhibition of autophagy
might be a novel therapeutic approach to the treatment of endometriosis.
This study was funded by the National Nature Science Foundation of China (grant number 81170545 and 81471439). The authors declare no competing interests.
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.
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