Kamo Hiroki, Kawahara Ryota, Simizu Siro
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Kanagawa 223-8522, Japan.
Oncol Lett. 2022 May;23(5):169. doi: 10.3892/ol.2022.13289. Epub 2022 Apr 6.
Melanoma is a type of skin cancer that derives from melanocytes; this tumor is highly metastatic and causes poor clinical outcomes in patients. Vasculogenic mimicry (VM), a vascular-like network that is formed by tumor cells instead of endothelial cells, promotes the growth and metastasis of tumors by providing tumors with oxygen- and nutrient-containing blood. VM correlates with a poor prognosis in patients with melanoma, but the melanoma-specific mechanisms of VM are unknown. The present study revealed that treatment with the melanogenesis stimulators 3-isobutyl 1-methylxanthine (IBMX) and α-melanocyte-stimulating hormone (α-MSH) significantly inhibited VM in MNT-1 human pigmented melanoma cells. Tyrosinase (TYR), an essential enzyme in melanin production, was upregulated on treatment with α-MSH and IBMX, prompting an examination of the association between TYR and VM. A TYR inhibitor, arbutin, promoted VM in melanoma cells. Furthermore, CRISPR/Cas9-mediated knockout (KO) of TYR increased VM by melanoma cells. Notably, even in non-pigmented melanoma cells, TYR attenuated VM. Although re-expression of wild-type TYR suppressed VM in TYR-KO cells, T373K TYR, a frequently detected mutation in individuals with albinism, failed to inhibit VM. Overall, these results demonstrated that TYR negatively regulates VM, providing novel insights into the antioncogenic function of TYR in melanomas.
黑色素瘤是一种起源于黑素细胞的皮肤癌；这种肿瘤具有高度转移性，会导致患者临床预后不良。血管生成拟态（VM）是一种由肿瘤细胞而非内皮细胞形成的类血管网络，通过为肿瘤提供含氧和营养的血液来促进肿瘤的生长和转移。VM与黑色素瘤患者的不良预后相关，但VM在黑色素瘤中的具体机制尚不清楚。本研究表明，用黑素生成刺激剂3-异丁基-1-甲基黄嘌呤（IBMX）和α-黑素细胞刺激激素（α-MSH）处理可显著抑制MNT-1人色素性黑色素瘤细胞中的VM。酪氨酸酶（TYR）是黑色素生成中的一种关键酶，在用α-MSH和IBMX处理后上调，这促使人们研究TYR与VM之间的关联。一种TYR抑制剂熊果苷可促进黑色素瘤细胞中的VM。此外，CRISPR/Cas9介导的TYR基因敲除（KO）增加了黑色素瘤细胞的VM。值得注意的是，即使在非色素性黑色素瘤细胞中，TYR也能减弱VM。虽然野生型TYR的重新表达可抑制TYR-KO细胞中的VM，但T373K TYR（白化病患者中常见的一种突变）却无法抑制VM。总体而言，这些结果表明TYR对VM具有负调控作用，为TYR在黑色素瘤中的抗癌功能提供了新的见解。
