Abstract
Vasculogenic mimicry (VM)‐positive melanomas are usually associated with poor prognosis. Rictor, the key component of the rapamycin‐insensitive complex of mTOR (mTORC2), is up‐regulated in several cancers, especially in melanomas with poor prognosis. The aim of this study was to investigate the role of Rictor in the regulation of VM and the mechanism underlying this possible regulation. VM channels were found in 35 of 81 tested melanoma samples and high Rictor expression correlated with VM structures. Moreover, Kaplan–Meier survival curves indicated that VM structures and high Rictor expression correlated with shorter survival in patients with melanoma. In vitro, Rictor knockdown by short hairpin RNA (shRNA) significantly inhibited the ability of A375 and MUM‐2B melanoma cells to form VM structures, as evidenced by most tubes remaining open. Cell cycle analysis revealed that Rictor knockdown blocked cell growth and resulted in the accumulation of cells in G2/M phase, and cell migration and invasion were greatly affected after Rictor down‐regulation. Western blotting assays indicated that down‐regulating Rictor significantly inhibited the phosphorylation of AKT at Ser473 and Thr308, which subsequently inhibited the expression and activity of downstream MMP‐2/9, as confirmed by real‐time PCR and gelatin Zymography. MK‐2206, a small‐molecule inhibitor of AKT, similarly inhibited the activity of AKT and secretion of MMP‐2/9, further supporting that Rictor down‐regulation inhibits the phosphorylation of AKT and activity of downstream MMP‐2/9 to affect VM formation. In conclusion, Rictor plays an important role in melanoma VM via the Rictor—AKT—MMP‐2/9 signalling pathway.
Highlights
Melanoma is the most serious type of skin cancer and is associated with an aggressive clinical course and poor prognosis
57 samples were defined as positive staining, among which 36 cases were accompanied with recurrence or metastasis, suggesting that the expression of rapamycin-insensitive companion of mTOR (Rictor) is elevated during melanoma tumorigenesis (P = 0.014; Table 1, Fig. 1Aa)
Our results support the hypothesis that Rictor plays an important role in the Vasculogenic mimicry (VM) formation of melanoma cells via the AKT-matrix metalloproteinases (MMPs)-2/9 pathway
Summary
Melanoma is the most serious type of skin cancer and is associated with an aggressive clinical course and poor prognosis. Previous studies have confirmed VM in several malignant tumours with poor survival [1], such as ovarian cancer [2], breast cancer [3], lung cancer [4], prostate cancer [5], glioma [6] and renal cell carcinoma [7]. VM describes the ability of highly invasive melanoma cells to express endothelium-associated genes and form extracellular matrix (ECM)rich vasculogenic-like channels in three-dimensional culture. VM, independent of endothelium-dependent vessels, invariably indicates poor prognosis and survival in the clinic [8]. The mammalian target of rapamycin (mTOR) plays an important role in cell proliferation and survival [17, 18]. Based on the sensitivity to rapamycin treatment, mTOR is separated into two distinct multiprotein complexes, a rapamycin-sensitive mTOR complex 1 (mTORC1)
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