Hypoxia induced epithelial-mesenchymal transition and vasculogenic mimicry formation by promoting Bcl-2/Twist1 cooperation.

Hypoxia plays a pivotal role in tumor progression. The functions of hypoxia and subsequent Bcl-2/Twist1 activation in epithelial-mesenchymal transition (EMT) and vasculogenic mimicry (VM) formation are currently unclear. This study aimed to investigate the role of Bcl-2/Twist1 cooperation in hypoxia-induced EMT and VM formation. In in vitro experiments, we found that hypoxia resulted in co-overexpression of Bcl-2 and Twist1, facilitated Twist1 nuclear translocation and promoted EMT and VM formation. Co-overexpression of Bcl-2 and Twist1 under normoxia could also induce EMT and promote VM formation. Furthermore, blocking Bcl-2 or Twist1 attenuated the effects of hypoxia on EMT progress and VM formation in hepatocellular carcinoma cells. In in vivo experiments, the mechanism by which hypoxia promoted Bcl-2 and Twist1 co-overexpression and induced EMT process and VM formation was demonstrated using murine xenograft models. These results above suggest that hypoxia could activate the cooperation of Bcl-2 and Twist1, Bcl-2 plays an important role in assisting Twist1 nuclear translocation which could change the expression of a wide range of genes and lead to the induction of EMT and VM formation.

Liu K ，Sun B ，Zhao X ，Wang X ，Li Y ，Qiu Z ，Gu Q ，Dong X ，Zhang Y ，Wang Y ，Zhao N ... -  《-》

Hypoxia promotes vasculogenic mimicry formation by the Twist1-Bmi1 connection in hepatocellular carcinoma.

Liu K ，Sun B ，Zhao X ，Wang X ，Li Y ，Qiu Z ，Liu T ，Gu Q ，Dong X ，Zhang Y ，Wang Y ，Zhao N ... -  《-》

Promotion of tumor cell metastasis and vasculogenic mimicry by way of transcription coactivation by Bcl-2 and Twist1: a study of hepatocellular carcinoma.

The antiapoptotic protein Bcl-2 plays multiple roles in apoptosis, immunity, and autophagy. Its expression in tumors correlates with tumor grade and malignancy. The recapitulation of the normal developmental process of epithelial-mesenchymal transition (EMT) contributes to tumor cell plasticity. This process is also a characteristic of metastatic cells and vasculogenic mimicry. In the present study we report functional and structural interactions between Bcl-2 and the EMT-regulating transcription factor Twist1 and the relationship with metastasis and vascular mimicry. Bcl-2 and Twist1 are coexpressed under hypoxia conditions. The Bcl-2 can bind to Twist1 in vivo and in vitro. This interaction involves basic helix-loop-helix DNA binding domain within Twist1 and through two separate domains within Bcl-2 protein. Formation of the Bcl-2/Twist1 complex facilitates the nuclear transport of Twist1 and leads to transcriptional activation of wide ranges of genes that can increase the tumor cell plasticity, metastasis, and vasculogenic mimicry. Finally, nuclear expression of Bcl-2 and Twist1 is correlated with poor survival of these patients in a cohort of 97 cases of human hepatocellular carcinoma. The results describe a novel function of Bcl-2 in EMT induction, provide insight into tumor progression, and implicate the Bcl-2/Twist1 complex as a potential target for developing chemotherapeutics.

Sun T ，Sun BC ，Zhao XL ，Zhao N ，Dong XY ，Che N ，Yao Z ，Ma YM ，Gu Q ，Zong WK ，Liu ZY ... -  《-》

Expression and functional significance of Twist1 in hepatocellular carcinoma: its role in vasculogenic mimicry.

Sun T ，Zhao N ，Zhao XL ，Gu Q ，Zhang SW ，Che N ，Wang XH ，Du J ，Liu YX ，Sun BC ... -  《-》

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

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

Du J ，Sun B ，Zhao X ，Gu Q ，Dong X ，Mo J ，Sun T ，Wang J ，Sun R ，Liu Y ... -  《-》