Ni Ting, Huang Ting, Gu Sheng-Lan, Wang Jing, Liu Yao, Sun Xiao, Wang Yu-Dong
Department of Gynecology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, No. 910 Hengshan Road, Shanghai 200030, China.
Laboratory for Gynecologic Oncology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, No. 910 Hengshan Road, Shanghai 200030, China.
J Cancer. 2020 Feb 10;11(9):2518-2528. doi: 10.7150/jca.40055. eCollection 2020.
: Perineural invasion (PNI) is correlated with negative prognosis in multiple cancers, but its role in endometrial cancer (EC) is still largely unknown; thus, targeted treatment for nerve infiltration is lacking as well. : The interaction between nerve and EC cells were investigated by in vitro neural invasion assay and transwell coculture system. Then the nerve-related receptor gene glutamate ionotropic receptor AMPA type subunit 2 (GRIA2) was detected in EC tissues and cells using PCR array, western blotting, and immunohistochemistry. The role of GluR2 (gene name GRIA2) on EC proliferation, migration and invasion was evaluated by a GluR2 antagonist and shRNA. At the same time, the neurotransmitter effect on GluR2 (glutamate) from the cocultured conditional medium was measured using high-performance liquid chromatography (HPLC). : EC cell line Ishikawa (ISK) showed the ability to migrate along neurites in vitro and the numbers of migrated/invaded EC cells in the DRG neuron coculture group were significantly increased. The expression of GluR2 in EC tissue was found to be higher than that in para-carcinoma tissue. After GluR2 antagonist and GluR2 shRNA treatment, the proliferation, migration and invasion of ISK cells was markedly inhibited. Moreover, the ability of DRG neurons to promote the migration and invasion of ISK cells could also be attenuated by downregulation of GluR2, and the concentration of the neurotransmitter glutamate was notably increased in the coculture conditional medium compared to that in the DRG neuron or ISK cells alone. : DRG neurons promote metastasis of EC cells via GluR2, which might be a risk factor for PNI in EC. Moreover, the perineural system may promote tumor invasion and metastasis under certain circumstances.
神经周围浸润（PNI）与多种癌症的不良预后相关，但其在子宫内膜癌（EC）中的作用仍 largely 未知；因此，针对神经浸润的靶向治疗也缺乏。通过体外神经侵袭试验和 Transwell 共培养系统研究神经与 EC 细胞之间的相互作用。然后使用 PCR 阵列、蛋白质印迹和免疫组织化学在 EC 组织和细胞中检测神经相关受体基因谷氨酸离子型受体 AMPA 型亚基 2（GRIA2）。通过 GluR2 拮抗剂和 shRNA 评估 GluR2（基因名 GRIA2）对 EC 增殖、迁移和侵袭的作用。同时，使用高效液相色谱（HPLC）测量共培养条件培养基中来自神经递质对 GluR2（谷氨酸）的影响。EC 细胞系 Ishikawa（ISK）在体外显示出沿神经突迁移的能力，并且在背根神经节（DRG）神经元共培养组中迁移/侵袭的 EC 细胞数量显著增加。发现 EC 组织中 GluR2 的表达高于癌旁组织。在 GluR2 拮抗剂和 GluR2 shRNA 处理后，ISK 细胞的增殖、迁移和侵袭明显受到抑制。此外，下调 GluR2 也可减弱 DRG 神经元促进 ISK 细胞迁移和侵袭的能力，并且与单独的 DRG 神经元或 ISK 细胞相比，共培养条件培养基中神经递质谷氨酸的浓度显著增加。DRG 神经元通过 GluR2 促进 EC 细胞转移，这可能是 EC 中 PNI 的一个危险因素。此外，神经周围系统在某些情况下可能促进肿瘤侵袭和转移。
