J Cancer 2019; 10(24):6065-6073. doi:10.7150/jca.33635

Research Paper

NT-3/TrkC Axis Contributes to the Perineural Invasion and the Poor Prognosis in Human Salivary Adenoid Cystic Carcinoma

Huan Li1*, Zihui Yang1*, Weiqi Wang1*, Jun Wang1, Jianying Zhang1, Junye Liu2, Tao Yang1, Yaowu Yang1, Jianhua Wei1, Delin Lei1✉, Xinjie Yang1✉

1. 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
2. Department of Radiation Medicine, Fourth Military Medical University, Xi'an 710032, China
*Contributed equally

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Citation:
Li H, Yang Z, Wang W, Wang J, Zhang J, Liu J, Yang T, Yang Y, Wei J, Lei D, Yang X. NT-3/TrkC Axis Contributes to the Perineural Invasion and the Poor Prognosis in Human Salivary Adenoid Cystic Carcinoma. J Cancer 2019; 10(24):6065-6073. doi:10.7150/jca.33635. Available from http://www.jcancer.org/v10p6065.htm

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Abstract

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 (P < 0.05). Additionally, the high expression of NT-3 was significantly associated with the poor prognosis of SACC patients (P < 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.

Keywords: NT-3, TrkC, salivary adenoid cystic carcinoma, Schwann cells, perineural invasion