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

• DOI: 10.1007/s00109-016-1452-x
• Publication Date: 2016-08-19T13:05:33Z
• Authors: Xian Lin; Ran Sun; Xiulan Zhao; Dongwang Zhu; Xueming Zhao; Qiang Gu; Xueyi Dong; Danfang Zhang; Yanhui Zhang; Yanlei Li; Baocun Sun
• Keywords: Adult; Male; 0303 health sciences; Epithelial-Mesenchymal Transition; Gene Expression; Middle Aged; Cadherins; Immunohistochemistry; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Cell Movement; Cell Line, Tumor; Animals; Heterografts; Humans; Female; Neoplasm Metastasis; Melanoma; Aged; Cell Proliferation; Neoplasm Staging

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.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.