Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.
Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul 03722, Korea.
Int J Mol Sci. 2019 Jan 28;20(3):555. doi: 10.3390/ijms20030555.
The expression of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2 (LINGO2) has been reported in Parkinson's disease; however, its role in other diseases is unknown. Gastric cancer is the second leading cause of cancer death. Cancer stem cells (CSC) are a subpopulation of cancer cells that contribute to the initiation and invasion of cancer. We identified LINGO2 as a CSC-associated protein in gastric cancers both in vitro and in patient-derived tissues. We studied the effect of LINGO2 on cell motility, stemness, tumorigenicity, and angiogenic capacity using cells sorted based on LINGO2 expression and LINGO2-silenced cells. Tissue microarray analysis showed that LINGO2 expression was significantly elevated in advanced gastric cancers. The overall survival of patients expressing high LINGO2 was significantly shorter than that of patients with low LINGO2. Cells expressing high LINGO2 showed elevated cell motility, angiogenic capacity, and tumorigenicity, while LINGO2 silencing reversed these properties. Silencing LINGO2 reduced kinase B (AKT)/extracellular signal-regulated kinase (ERK)/ERK kinase (MEK) phosphorylation and decreased epithelial-mesenchymal transition (EMT)-associated markers-N-Cadherin and Vimentin and stemness-associated markers- POU class 5 homeobox 1 (OCT4) and Indian hedgehog (IHH), and markedly decreased the CD44⁺ population. These indicate the involvement of LINGO2 in gastric cancer initiation and progression by altering cell motility, stemness, and tumorigenicity, suggesting LINGO2 as a putative target for gastric cancer treatment.
富含亮氨酸重复和免疫球蛋白样结构域的神经生长抑制因子受体相互作用蛋白 2（LINGO2）的表达已在帕金森病中报道；然而，其在其他疾病中的作用尚不清楚。胃癌是癌症死亡的第二大主要原因。癌症干细胞（CSC）是癌细胞的一个亚群，有助于癌症的起始和侵袭。我们在体外和患者来源的组织中鉴定出 LINGO2 是胃癌中的一种 CSC 相关蛋白。我们使用基于 LINGO2 表达和 LINGO2 沉默细胞分选的细胞研究了 LINGO2 对细胞迁移、干性、致瘤性和血管生成能力的影响。组织微阵列分析显示，LINGO2 在晚期胃癌中的表达显著升高。表达高 LINGO2 的患者的总生存期明显短于表达低 LINGO2 的患者。表达高 LINGO2 的细胞表现出更高的细胞迁移、血管生成能力和致瘤性，而 LINGO2 沉默则逆转了这些特性。沉默 LINGO2 降低了蛋白激酶 B（AKT）/细胞外信号调节激酶（ERK）/ERK 激酶（MEK）磷酸化，并降低了上皮-间充质转化（EMT）相关标志物-N-钙粘蛋白和波形蛋白以及干性相关标志物-POU 类 5 同源框 1（OCT4）和印度刺猬（IHH），并显著减少了 CD44⁺ 群体。这些表明 LINGO2 通过改变细胞迁移、干性和致瘤性参与胃癌的发生和进展，提示 LINGO2 可能成为胃癌治疗的潜在靶点。
