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C-myc overexpression drives melanoma metastasis by promoting vasculogenic mimicry via c-myc/snail/Bax signaling

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Abstract

c-Myc is a well-characterized proto-oncogene that induces cellular transformation and modulates programmed cell death. While recent studies have demonstrated high expression of c-Myc protein in advanced and metastatic melanoma, the clinical and biological implications remain to be fully elucidated. In this study, we investigated the effect of c-Myc overexpression in melanoma tumorigenesis. Clinicopathological analysis demonstrated that c-Myc expression positively correlated with the formation of vasculogenic mimicry (VM) and linearly patterned programmed cell necrosis (LPPCN). Clinically, high c-Myc expression was significantly associated with distant metastasis and poor prognosis, while biologically, c-Myc overexpression led to significant increases in cell motility, invasiveness and metastasis. Moreover, c-Myc induced the formation of VM and promoted the expression of epithelial-mesenchymal transition (EMT)-associated protein Snail both in vivo and in vitro. High expression of c-Myc increased Bax expression in hypoxic conditions and induced cell apoptosis. Taken together, we conclude that c-Myc overexpression promotes the formation of VM by EMT and LPPCN in melanoma. Our improved understanding of the clinical and biological effects of c-Myc overexpression in melanoma highlights the incomplete understanding of this oncogene, and indicates that c-Myc is a potential therapeutic target of this disease.

Key message

  • High c-Myc expression is associated with tumor metastasis and poor prognosis in human melanoma.

  • c-Myc upregulates Snail expression to promote EMT via the TGF-β/Snail/Ecadherin signal pathway.

  • c-Myc leads to cell death by upregulating Bax expression causing a lower Bcl2/Bax ratio under severe hypoxic conditions.

  • c-Myc promotes vasculogenic mimicry and linearly patterned programmed cell necrosis.

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Acknowledgment

This study was partly supported by the follow grants:

1) Key project of the National Natural Science Foundation of China (NO. 81230050);

2) The National Natural Science Foundation of China (NO. 81172046);

3) The National Natural Science Foundation of China (NO. 81173091);

4) The National Basic Research Program of China (973 Program, NO. 2010CB529403).

Author contribution statement

B.C.S. conceived the study, B.C.S., R.S. and X.L. designed experiments and wrote the manuscript. X.L., X.L.Z., X.M.Z., Q.G. and X.Y.D. performed experiments. D.W.Z. and D.F.Z. analyzed the data, Y.H.Z., R.S. and Y.L.L. collected the human pathological specimen of melanoma. All authors revised the manuscript.

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Authors and Affiliations

  1. Department of Pathology, Tianjin Medical University, Tianjin, 300070, China

    Xian Lin, Xiulan Zhao, Xueming Zhao, Qiang Gu, Xueyi Dong, Danfang Zhang, Yanlei Li & Baocun Sun

  2. Department of Surgery, Tianjin Hospital of ITCWM Nankai Hospital, Tianjin, 300100, China

    Ran Sun

  3. Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, 300060, China

    Yanhui Zhang & Baocun Sun

  4. Department of Surgery, Stomatological Hospital of Tianjin Medical University, Tianjin, 300070, China

    Dongwang Zhu

  5. Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China

    Xiulan Zhao, Qiang Gu & Baocun Sun

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  1. Xian Lin
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  11. Baocun Sun
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Correspondence to Baocun Sun.

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Xian Lin and Ran Sun contributed equally to this work.

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Lin, X., Sun, R., Zhao, X. et al. C-myc overexpression drives melanoma metastasis by promoting vasculogenic mimicry via c-myc/snail/Bax signaling. J Mol Med 95, 53–67 (2017). https://doi.org/10.1007/s00109-016-1452-x

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  • DOI: https://doi.org/10.1007/s00109-016-1452-x

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