Division of Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK.
Queen Charlotte and Chelsea Hospital, London W120HS, UK.
Int J Mol Med. 2019 Jan;43(1):47-56. doi: 10.3892/ijmm.2018.3967. Epub 2018 Oct 31.
Endometriosis is a well‑known risk factor for ovarian cancer. The genetic changes that characterise endometriosis are poorly understood; however, the mechanistic target of rapamycin (mTOR) pathway is involved. In this study, we investigated the expression of key mTOR components in endometriosis and the effects of rapalogues using an endometrioid ovarian carcinoma cell line (MDAH 2774) as an in vitro model. Gene expression of mTOR, DEPTOR, Rictor and Raptor was assessed by qPCR in 24 endometriosis patients and in silico in ovarian cancer patients. Furthermore, the effects of Rapamycin, Everolimus, Deforolimus, Temsirolimus, Resveratrol, and BEZ235 (Dactolisib, a dual kinase inhibitor) on mTOR signalling components was assessed. mTOR showed a significant increase in the expression in endometriosis and ovarian endometrioid adenocarcinoma patients compared to non‑affected controls. DEPTOR, an inhibitor of mTOR, was downregulated in the advanced stages of ovarian cancer (III and IV) compared to earlier stages (I and II). Treatment of MDAH‑2774 cells with the mTOR inhibitors resulted in the significant upregulation of DEPTOR mRNA, whereas treatment with rapamycin and BEZ‑235 (100 nM) resulted in downregulation of the mTOR protein expression after 48 h of treatment. None of the treatments resulted in translocation of mTOR from cytoplasm to nucleus. Upregulation of DEPTOR is a positive prognostic marker in ovarian cancer and is increased in response to mTOR pathway inhibition suggesting that it functions as a tumour suppressor gene in endometrioid ovarian carcinoma. Collectively, our data suggest the mTOR pathway as a potential connection between endometriosis and ovarian cancer and may be a potential target in the treatment of both conditions.
子宫内膜异位症是卵巢癌的一个已知危险因素。导致子宫内膜异位症的遗传变化尚不清楚；然而，雷帕霉素（mTOR）途径的机械靶向是涉及其中的。在这项研究中，我们研究了子宫内膜异位症中关键 mTOR 成分的表达以及使用子宫内膜样卵巢癌细胞系（MDAH 2774）作为体外模型的雷帕霉素类似物的作用。通过 qPCR 在 24 名子宫内膜异位症患者和卵巢癌患者的体内评估 mTOR、DEPTOR、Rictor 和 Raptor 的基因表达。此外，还评估了雷帕霉素、依维莫司、地氟莫司、替西罗莫司、白藜芦醇和 BEZ235（双重激酶抑制剂，达特利司布）对 mTOR 信号成分的影响。与非受影响的对照组相比，mTOR 在子宫内膜异位症和卵巢子宫内膜样腺癌患者中的表达显著增加。DEPTOR 是 mTOR 的抑制剂，在卵巢癌的晚期（III 和 IV 期）与早期（I 和 II 期）相比下调。用 mTOR 抑制剂处理 MDAH-2774 细胞导致 DEPTOR mRNA 的显著上调，而用雷帕霉素和 BEZ-235（100 nM）处理导致 mTOR 蛋白表达在 48 小时后下调。这些处理都没有导致 mTOR 从细胞质易位到细胞核。DEPTOR 的上调是卵巢癌的一个阳性预后标志物，并且对 mTOR 途径抑制有反应，表明其在子宫内膜样卵巢癌中作为肿瘤抑制基因发挥作用。总的来说，我们的数据表明 mTOR 途径是子宫内膜异位症和卵巢癌之间的潜在联系，并且可能是这两种疾病治疗的潜在靶点。
