Li Huan, Yang Zihui, Wang Weiqi, Wang Jun, Zhang Jianying, Liu Junye, Yang Tao, Yang Yaowu, Wei Jianhua, Lei Delin, Yang Xinjie
State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi'an 710032, China.
Department of Radiation Medicine, Fourth Military Medical University, Xi'an 710032, China.
J Cancer. 2019 Oct 15;10(24):6065-6073. doi: 10.7150/jca.33635. eCollection 2019.
The present study was aimed to investigate the role and mechanism of neurotrophin-3 (NT-3) and its specific receptor tropomyosin receptor kinase C (TrkC) in the perineural invasion (PNI) process of the salivary adenoid cystic carcinoma (SACC). The co-cultured system between SACC cells and Schwann cells (SCs) was employed to detect the expression of NT-3 and TrkC. The results of ELISA, qRT-PCR and western blot showed that NT-3 was noticeably elevated in the co-cultured SACC-83 cells, while TrkC was increased in the co-cultured SCs. The results of scratch wound healing, migration, and 3D co-culture assays showed that the directional migration abilities of the co-cultured SACC-83 cells and SCs were significantly increased. Under the stimulation of NT-3, the directional motor ability of SACC-83 cells and SCs was significantly improved, and the apoptosis of SACC-83 cells and SCs were obviously inhibited. In addition, blocking TrkC by its specific inhibitor AZD7451 could significantly inhibit these effects. Immunohistochemistry staining showed that the positive expression of NT-3 (88.5%) and TrkC (92.3%) was significantly correlated with the PNI in SACC specimens ( < 0.05). Additionally, the high expression of NT-3 was significantly associated with the poor prognosis of SACC patients ( < 0.05). The present study indicated that NT-3/TrkC axis contributed to the PNI progression and the poor prognosis of SACC via regulating the interaction between SACC cells and SCs. Interruption of the interaction between SACC cells and SCs by blocking the NT-3/TrkC axis might be an effective strategy for anti-PNI therapy in SACC.
本研究旨在探讨神经营养因子-3（NT-3）及其特异性受体原肌球蛋白受体激酶C（TrkC）在涎腺腺样囊性癌（SACC）神经周浸润（PNI）过程中的作用及机制。采用SACC细胞与雪旺细胞（SCs）共培养体系检测NT-3和TrkC的表达。ELISA、qRT-PCR和蛋白质印迹结果显示，共培养的SACC-83细胞中NT-3明显升高，而共培养的SCs中TrkC增加。划痕伤口愈合、迁移和三维共培养试验结果显示，共培养的SACC-83细胞和SCs的定向迁移能力显著增强。在NT-3刺激下，SACC-83细胞和SCs的定向运动能力显著提高，SACC-83细胞和SCs的凋亡明显受到抑制。此外，用其特异性抑制剂AZD7451阻断TrkC可显著抑制这些作用。免疫组织化学染色显示，NT-3（88.5%）和TrkC（92.3%）的阳性表达与SACC标本中的PNI显著相关（<0.05）。此外，NT-3的高表达与SACC患者的不良预后显著相关（<0.05）。本研究表明，NT-3/TrkC轴通过调节SACC细胞与SCs之间的相互作用促进了SACC的PNI进展和不良预后。通过阻断NT-3/TrkC轴中断SACC细胞与SCs之间的相互作用可能是SACC抗PNI治疗的有效策略。
