title: C-myc overexpression drives melanoma metastasis by promoting vasculogenic mimicry via c-myc/snail/Bax signaling.
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.
  
  
  
  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.
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Surgery, Tianjin Hospital of ITCWM Nankai Hospital, Tianjin, 300100, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Sun
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.|Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Surgery, Stomatological Hospital of Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Dongwang
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Xueming
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.|Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Xueyi
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Danfang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, 300060, China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Yanlei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China. baocunsun@aliyun.com.|Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, 300060, China. baocunsun@aliyun.com.|Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China. baocunsun@aliyun.com.
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D015820:Cadherins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D000071250:Snail Family Transcription Factors; D016212:Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein
keywords: Linearly patterned programmed cell necrosis; Vasculogenic mimicry; c-Myc