Jing Du1, Baocun Sun2, Xiulan Zhao3, Qiang Gu3, Xueyi Dong3, Jing Mo4, Tao Sun4, Junyan Wang4, Ran Sun4, Yanrong Liu4. 1. 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. 2. 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. Electronic address: baocunsun@gmail.com. 3. Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China; Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin 300070, PR China. 4. Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China.
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.
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.