Hypoxia-inducible factor-1α promotes endometrial stromal cells migration and invasion by upregulating autophagy in endometriosis

Abstract

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.

In vitro and in vivo effects of MK2206 and chloroquine combination therapy on endometriosis: autophagy may be required for regrowth of endometriosis

“…(), patients with endometriosis may benefit from a sequential approach in which autophagy is selectively inhibited in endometriotic cells, diseased cells, and then selectively activated in endometrial cells, non‐diseased cells, after discontinuation of drug treatment. However, to date, only a few studies have investigated the role of autophagy in endometriosis, as well as in the endometrium, and the results remain controversial (Choi et al ., ; Allavena et al ., ; Mei et al ., ; Ruiz et al ., ; Liu et al ., ). Further studies are required to determine whether long‐term inhibition of autophagy prevents recurrence of endometriosis after discontinuation of drug treatment and whether it results in any adverse effects on the endometrium of patients with endometriosis.…”

Long non‐coding RNA MALAT1 mediates hypoxia‐induced pro‐survival autophagy of endometrial stromal cells in endometriosis

“…We purified primary human endometrial stromal cells as described previously with slight modification . Briefly, washed endometrium tissues were minced into 1‐ to 2‐mm pieces with a sterile surgical scissors and digested in PBS containing 2 mg/mL of type II collagenase (0.1%, Sigma‐Aldrich, USA) for 45‐60 minutes at 37°C with constant agitation.…”

“…It is generally believed that autophagy plays a crucial role in protecting cells to survival by preventing apoptosis under various metabolic stresses microenvironment, such as hypoxia or oxidative stress . Interestingly, our previous studies as well as others revealed that autophagic process was up‐regulated in ovarian endometriomas . However, 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.…”

Roles of cell migration and invasion mediated by Twist in endometriosis

“…Sampson's retrograde menstruation hypothesis does not fully explain why most women suffer from retrograde menstruation but only 10 percent of them finally develop endometriosis. Researchers have found that other factors such as altered microenvironment may contribute to the development of endometriosis . In the current study, we compared the expression of Twist, E‐cadherin and N‐cadherin in ectopic endometrium and eutopic endometrium of ovarian endometriosis and normal endometrium of nonendometriosis patients, as well as the changes of migration and invasion of endometrial stromal cells after transfection of Twist genes.…”