A novel PI3K/AKT signaling axis mediates Nectin-4-induced gallbladder cancer cell proliferation, metastasis and tumor growth
A novel PI3K/AKT signaling axis mediates Nectin-4-induced gallbladder cancer cell proliferation, metastasis and tumor growth
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新型 PI3K/AKT 信号轴介导 Nectin-4 诱导的胆囊癌细胞增殖、转移和肿瘤生长
DOI：
10.1016/j.canlet.2016.02.049
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发表时间：
2016-05-28
期刊：
影响因子：
9.7
通讯作者：
Liu, Yingbin
中科院分区：
文献类型：
--
作者：
Zhang, Yijian;Liu, Shibo;Liu, Yingbin
Nectin-4 是一种不依赖 Ca2+ 的免疫球蛋白样细胞粘附分子，通过亲同性和异嗜性相互作用在细胞间粘附中具有多种功能。细胞间粘附过程对于细胞极化、分化、增殖、存活和运动至关重要。在这里，我们报告 Nectin-4 在胆囊癌 (GBC) 中显着过度表达，胆囊癌是最常见的胆道恶性肿瘤，局部肿瘤扩散和侵袭的风险很高。此外，GBC患者中Nectin-4的高表达与病理T分期和淋巴结转移状态相关，下游靶点Rac1的表达水平和不良预后也与Nectin-4相关。 Nectin-4 的异位表达促进小鼠模型中 GBC 细胞的生长、运动和肿瘤生长。 Nectin-4 的消耗抑制了细胞培养物和小鼠中 GBC 细胞的增殖和迁移。我们的数据表明，PI3K/AKT 通路的激活参与了 Nectin-4 在 GBC 中激活 Rac1 的致癌功能。用 LY294002 抑制 PI3K/AKT 和/或用 NSC23766 抑制 Rac1 会损害 Nectin-4 介导的 GBC 细胞增殖和运动。我们假设 Nectin-4 通过 Rac1 的 PI3K/AKT 通路激活对 GBC 进展至关重要。 Nectin-4可能是GBC患者新的预后因素和治疗靶点。 (C) 2016 Elsevier Ireland Ltd. 保留所有权利。
Nectin-4 is a Ca2+-independent immunoglobulin-like cell adhesion molecule which has diverse functions in cell-cell adhesion via homophilic and heterophilic interactions. Cell-cell adhesive processes are central to cell polarization, differentiation, proliferation, survival and movement. Here we report that Nectin-4 is substantially overexpressed in gallbladder cancer (GBC), the most common biliary tract malignancy with a high risk of local tumor spread and invasion. Further, Nectin-4 high expression in GBC patients was associated with pathologic T stage and lymph node metastasis status, and the expression level of the downstream target Rac1 and poor prognoses were also correlated with Nectin-4. Ectopic expression of Nectin-4 promoted GBC cell growth, motility and tumor growth in a mouse model. The depletion of Nectin-4 inhibited GBC cell proliferation and migration both in cell culture and in mice. Our data suggest that activation of the PI3K/AKT pathway was involved in the oncogenic function of Nectin-4 to activate Rac1 in GBC. Inhibition of PI3K/AKT with LY294002 and/or Rac1 with NSC23766 impaired Nectin-4-mediated GBC cell proliferation and motility. We hypothesize that Nectin-4 is critical for GBC progression via PI3K/AKT pathway activation of Rac1. Nectin-4 may be a novel prognostic factor and therapeutic target in GBC patients. (C) 2016 Elsevier Ireland Ltd. All rights reserved.