缺氧通过诱导卵巢癌中的上皮-间充质转化促进血管生成拟态形成。

Hypoxia promotes vasculogenic mimicry formation by inducing epithelial-mesenchymal transition in ovarian carcinoma.

机构信息

Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China; Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin 300070, PR China; Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics, Tianjin 300100, PR China.

Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China; Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin 300070, PR China; Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin 300070, PR China.

出版信息

Gynecol Oncol. 2014 Jun;133(3):575-83. doi: 10.1016/j.ygyno.2014.02.034. Epub 2014 Feb 28.

DOI:10.1016/j.ygyno.2014.02.034

PMID:24589413

Abstract

OBJECTIVES

The functions of hypoxia and subsequent hypoxia-inducible factor-1α (HIF-1α) activation in vasculogenic mimicry (VM) are currently unclear. This study aimed to investigate the effects of hypoxia on VM formation in ovarian cancer, and explore the possible mechanism involved.

METHODS

The expression levels of HIF-1α, E-cadherin, vimentin, Twist1, Slug, and VE-cadherin proteins were analyzed by immunohistochemistry in 71 specimens of epithelial ovarian cancer. The results were correlated with VM and survival analysis. We used a well-established in vitro model of a three-dimensional culture to compare VM formation under hypoxia and normoxia in ovarian cancer cell lines SKOV3 and OVCAR3. To explore the potential mechanism, we examined the effects of hypoxia on the mRNA and protein expression levels of both E-cadherin and vimentin.

RESULTS

HIF-1α expression was correlated with loss of E-cadherin expression and up-regulated vimentin expression in 11 of the 18 VM-positive patients. Ovarian cancer with evidence of VM was significantly more likely to have high Twist1, Slug, and VE-cadherin expression levels. VM was observed in vitro under hypoxia. The ovarian cancer cells presented morphological epithelial-mesenchymal transition (EMT)-like changes (more fibroblastoid morphology and loss of cellular cohesiveness) under hypoxic conditions. The mRNA and protein levels demonstrated the induction of EMT after hypoxia. Clinicopathological analysis revealed that both VM and HIF-1α expression levels presented shorter survival durations.

CONCLUSIONS

Hypoxia contributed to VM formation by inducing EMT. These results may offer new insights for consideration in ovarian cancer treatment strategies.

摘要

目的

缺氧及其后续诱导因子-1α（HIF-1α）激活在血管生成拟态（VM）中的作用目前尚不清楚。本研究旨在探讨缺氧对卵巢癌中 VM 形成的影响，并探讨可能涉及的机制。

方法

采用免疫组织化学法检测 71 例上皮性卵巢癌组织中 HIF-1α、E-钙黏蛋白、波形蛋白、Twist1、Slug 和 VE-钙黏蛋白蛋白的表达水平，与 VM 及生存分析进行相关性分析。我们使用建立良好的体外三维培养模型，比较缺氧和常氧条件下卵巢癌细胞系 SKOV3 和 OVCAR3 中 VM 的形成。为了探讨潜在机制，我们检测了缺氧对 E-钙黏蛋白和波形蛋白 mRNA 和蛋白表达水平的影响。

结果

HIF-1α的表达与 18 例 VM 阳性患者中的 11 例 E-钙黏蛋白表达缺失和波形蛋白表达上调相关。有 VM 证据的卵巢癌更可能有高 Twist1、Slug 和 VE-钙黏蛋白表达。在体外缺氧条件下观察到 VM。卵巢癌细胞在缺氧条件下呈现出形态上的上皮-间充质转化（EMT）样变化（更具成纤维细胞样形态和细胞黏附性丧失）。缺氧后 mRNA 和蛋白水平显示诱导了 EMT。临床病理分析显示，VM 和 HIF-1α表达水平均与较短的生存时间相关。