Hashiguchi Shiho, Tanaka Tomoko, Mano Ryosuke, Kondo Seiji, Kodama Shohta
Department of Oral Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
Anticancer Res. 2025 Jan;45(1):65-71. doi: 10.21873/anticanres.17393.
BACKGROUND/AIM: In a tongue-submandibular lymph node (SLN) metastasis model, the cystine/glutamate transporter solute carrier family 7, member 11 (Slc7a11), also known as xCT, was found to increase in lymphatic endothelial cells (LECs) within SLNs prior to melanoma cell metastasis. However, the precise mechanism by which xCT influences LECs remains unclear. This study aimed to explore the role of xCT in primary cultured LECs.
To determine whether xCT is involved in cystine uptake and glutathione (GSH) synthesis in primary cultured LECs, cystine uptake and GSH assays were conducted. The antioxidant role of xCT was evaluated by measuring intracellular reactive oxygen species (ROS). Additionally, xCT expression was analyzed in human melanoma metastatic lymph nodes using immunohistochemical staining.
Slc7a11-knockdown LECs exhibited significantly reduced cystine uptake and intracellular GSH levels. ROS levels in Slc7a11-knockdown LECs were found to be increased compared to those in control LECs under HO-induced oxidative stress conditions. xCT stability is regulated by CD44v; therefore, we evaluated whether LYVE-1, a hyaluronic acid receptor in LECs, regulates xCT expression. LYVE-1 upregulates Slc7a11 mRNA expression, increasing GSH production in LECs. Furthermore, xCT expression was observed in LECs within human melanoma metastatic lymph nodes.
xCT functions as a cystine transporter, contributing to increased GSH levels in lymphatic fluid in melanoma metastasis.
背景/目的：在舌-下颌下淋巴结（SLN）转移模型中，发现胱氨酸/谷氨酸转运体溶质载体家族7成员11（Slc7a11），也称为xCT，在黑色素瘤细胞转移之前，SLN内的淋巴管内皮细胞（LEC）中表达增加。然而，xCT影响LEC的确切机制仍不清楚。本研究旨在探讨xCT在原代培养的LEC中的作用。
为了确定xCT是否参与原代培养的LEC中的胱氨酸摄取和谷胱甘肽（GSH）合成，进行了胱氨酸摄取和GSH检测。通过测量细胞内活性氧（ROS）来评估xCT的抗氧化作用。此外，使用免疫组织化学染色分析人黑色素瘤转移淋巴结中xCT的表达。
Slc7a11基因敲低的LEC表现出胱氨酸摄取和细胞内GSH水平显著降低。在HO诱导的氧化应激条件下，发现Slc7a11基因敲低的LEC中的ROS水平比对照LEC中的ROS水平升高。xCT稳定性受CD44v调节；因此，我们评估了LEC中的透明质酸受体LYVE-1是否调节xCT表达。LYVE-1上调Slc7a11 mRNA表达，增加LEC中的GSH产生。此外，在人黑色素瘤转移淋巴结内的LEC中观察到xCT表达。
xCT作为胱氨酸转运体发挥作用，有助于黑色素瘤转移时淋巴液中GSH水平升高。
