Department of Neurology, Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Department of Surgery, City of Hope National Medical Center, Duarte, California.
Neuro Oncol. 2020 Sep 29;22(9):1315-1326. doi: 10.1093/neuonc/noaa032.
Lymphocyte antigen 6 complex, locus K (LY6K) is a putative oncogene in various cancers. Elevated expression of LY6K is correlated with poor patient prognosis in glioblastoma (GBM). The aim of this study is to advance our understanding of the mechanism by which LY6K contributes to GBM tumor biology.
Bioinformatic data mining was used to investigate LY6K expression in relation to GBM clinical outcome. To understand the role of LY6K in GBM, we utilized patient-derived glioma stemlike cells (GSCs) and U87 cells and employed immunoblotting, immunofluorescent staining, radiation treatment, and orthotopic GBM xenograft models.
Our results show that increased expression of LY6K inversely correlates with GBM patient survival. LY6K promotes tumorigenicity in GBM cells both in vitro and in vivo. The mechanism underlying this tumorigenic behavior is enhancement of extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling. Interestingly, we observed that tumor-promoting LY6K-ERK1/2 signaling is mediated by the interaction of LY6K with caveolin-1, rather than through oncogenic receptor tyrosine kinase-mediated signaling. Moreover, association of LY6K with the cell membrane is crucial for its tumorigenic functions. Finally, DNA methylation maintains LY6K silencing, and hypomethylation of the LY6K promoter increases its expression. In GSCs, ionizing radiation leads to demethylation of the LY6K promoter, thereby increasing LY6K expression and GSC resistance to radiation.
Our study highlights the importance of the contribution of LY6K to GBM tumor biology and suggests LY6K as a potential membrane target for treating GBM.
淋巴细胞抗原 6 复合体，基因座 K（LY6K）是多种癌症中的一个假定癌基因。LY6K 的高表达与胶质母细胞瘤（GBM）患者的不良预后相关。本研究旨在深入了解 LY6K 促进 GBM 肿瘤生物学的机制。
生物信息学数据挖掘用于研究 LY6K 表达与 GBM 临床结局的关系。为了了解 LY6K 在 GBM 中的作用，我们利用患者来源的神经胶质瘤干细胞（GSCs）和 U87 细胞，并采用免疫印迹、免疫荧光染色、放射治疗和原位 GBM 异种移植模型。
我们的结果表明，LY6K 的表达增加与 GBM 患者的生存呈负相关。LY6K 在体外和体内均促进 GBM 细胞的致瘤性。这种致瘤行为的机制是增强细胞外信号调节激酶 1 和 2（ERK1/2）信号。有趣的是，我们观察到促进肿瘤发生的 LY6K-ERK1/2 信号是通过 LY6K 与窖蛋白-1 的相互作用介导的，而不是通过致癌受体酪氨酸激酶介导的信号。此外，LY6K 与细胞膜的结合对于其致瘤功能至关重要。最后，DNA 甲基化维持 LY6K 的沉默，而 LY6K 启动子的低甲基化增加其表达。在 GSCs 中，电离辐射导致 LY6K 启动子去甲基化，从而增加 LY6K 表达和 GSC 对辐射的抵抗力。
本研究强调了 LY6K 对 GBM 肿瘤生物学的重要贡献，并表明 LY6K 是治疗 GBM 的潜在膜靶标。
