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Hypoxia-induced vasculogenic mimicry formation via VE-cadherin regulation by Bcl-2

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Abstract

Vasculogenic mimicry (VM) refers to the unique ability of highly aggressive tumor cells to mimic the pattern of embryonic vasculogenic networks. Hypoxia plays a pivotal role in the formation of VM. Hypoxia-induced Bcl-2 overexpression is observed in many types of tumors including melanoma, in which it is associated with tumorigenicity and angiogenesis. VE-cadherin, the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation, is also overexpressed in melanoma. Despite these connections, whether hypoxia induces VM formation via VE-cadherin regulation by Bcl-2 is not confirmed. We used human melanoma cells to upregulate or knockdown the expression of Bcl-2 to investigate the possible molecular mechanism of VM formation under hypoxia. Bcl-2 overexpression increased VE-cadherin expression and VM formation under normoxia, whereas Bcl-2 siRNA significantly decreased VE-cadherin expression and VM formation under hypoxia. We then demonstrated that Bcl-2 regulated VE-cadherin transcription activity by Western blot, three-dimensional cultures, reporter gene assay, and clinical analysis. Therefore, Bcl-2-dependent VE-cadherin overexpression may be an important mechanism by which hypoxia induces VM.

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Acknowledgments

This study was supported by the Key Project of National Nature Science Foundation of China (No. 30830049), Project of National Nature Science Foundation of China (No. 81173091 and No. 81172046), the cooperation of China–Sweden (No. 09ZCZD SF04400), the Research Fund for the Doctoral Program of High Education (No. 20111202110010), the ‘‘211 Project’’ Graduate Innovation Grant of Tianjin Medical University (No. 146-200002), Key project of the Tianjin Natural Science Foundation (No. 12JCZDJC23600) and the Natural Science Foundation of Tianjin Education Commission (No. 20100104).

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All authors have read and approved the article before submission to your journal. There is no conflict of interest of any authors in relation to the submission.

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Authors and Affiliations

  1. Department of Pathology, Tianjin Medical University, Heping District Qixiangtai Road No. 22, Tianjin, 300070, People’s Republic of China

    Nan Zhao, Bao-cun Sun, Tao Sun, Yue-mei Ma, Xiu-lan Zhao, Xue-yi Dong, Na Che, Jing Mo & Qiang Gu

  2. Department of Pathology, Cancer Hospital, Tianjin Medical University, Tianjin, People’s Republic of China

    Bao-cun Sun & Zhi-yong Liu

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  1. Nan Zhao
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  2. Bao-cun Sun
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Correspondence to Bao-cun Sun.

Additional information

Nan Zhao, Bao-cun Sun, and Tao Sun contributed equally to this work.

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Zhao, N., Sun, Bc., Sun, T. et al. Hypoxia-induced vasculogenic mimicry formation via VE-cadherin regulation by Bcl-2. Med Oncol 29, 3599–3607 (2012). https://doi.org/10.1007/s12032-012-0245-5

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  • DOI: https://doi.org/10.1007/s12032-012-0245-5

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