Abstract
Vasculogenic mimicry (VM) constitutes a novel approach for tumour blood supply and contributes to tumour metastasis and poor prognosis in patients with melanoma. Myoferlin (MYOF), a type II membrane protein involved in membrane regeneration and repair, is elevated in several malignant tumours, especially in advanced melanomas. This study aims to investigate the role and mechanism of MYOF in the regulation of VM. VM structures were found in 14 of 52 tested melanoma samples, and high MYOF expression correlated with VM structures. According to Kaplan–Meier survival curves, VM channels and elevated MYOF expression both correlated with poor prognosis in melanoma patients. Down‐regulation of MYOF by siRNA severely impaired the capability of A375 cells to form VM structures in vitro. Further studies demonstrated MYOF knockdown inhibited cell migration and invasion, which is required for VM formation, via decreasing MMP‐2 expression as evidenced by Western blotting, RT‐RCP and ELISA results. SB‐3CT, a specific inhibitor of MMP‐2, showed similar inhibiting effects with siMYOF, further supporting that MYOF down‐regulation inhibits MMP‐2 expression to affect VM formation. Moreover, MYOF knockdown suppress VM formation by A375 cells by inducing mesenchymal‐to‐epithelial transition (MET). After down‐regulating MYOF, focal adhesions were enlarged and A375 cells developed into a clear epithelial morphology. Such cells acquired the expression of E‐cadherin at adherens junctions along with a loss of mesenchymal markers, such as Vimentin and Twist1. In conclusion, MYOF plays an important role in VM and knockdown of MYOF suppresses VM formation via decreasing MMP‐2 and inducing MET in A375 melanoma cells.
Highlights
Melanoma is the most aggressive type of skin cancer and is always associated with poor prognosis
MYOF-positive staining was found in 22 samples, among which 17 cases were accompanied with recurrence or metastasis, suggesting that MYOF is overexpressed during melanoma tumorigenesis (Table 1, Fig. 1A)
Vasculogenic mimicry (VM) is a marker of poor prognosis and contributes to tumour metastasis in several types of cancers, such as prostate cancer, [29] hepatocellular carcinoma, [30] gastric carcinoma [31] and invasive melanoma
Summary
Melanoma is the most aggressive type of skin cancer and is always associated with poor prognosis. VM was firstly reported in highly aggressive uveal melanomas by Maniotis in 1999 [1]. VM has been found in several types of malignant tumours such as breast cancer, liver cancer, glioma, ovarian cancer, prostate cancer and bidirectional differentiated malignant tumours [2]. VM describes the ability of highly invasive melanoma cells to express endotheliumassociated genes and form extracellular matrix (ECM)-rich vasculogenic-like channels in three-dimensional culture [3]. VM, formed by tumour cells instead of endothelial cells, invariably indicates poor prognosis and survival in the clinic [4]. The molecular mechanisms underlying this unique process are not fully clear, but matrix a 2017 The Authors
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