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Sympathetic innervation contributes to perineural invasion of salivary adenoid cystic carcinoma via the β2-adrenergic receptor

Authors Ma C, Gao T, Ju J, Zhang Y, Ni Q, Li Y, Zhao Z, Chai J, Yang X, Sun M

Received 17 October 2018

Accepted for publication 17 January 2019

Published 21 February 2019 Volume 2019:12 Pages 1475—1495


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 2

Editor who approved publication: Dr Leo Jen-Liang Su

Chao Ma,1,* Tao Gao,1,2,* Jun Ju,3,* Yi Zhang,4 Qianwei Ni,5 Yun Li,1 Zhenyan Zhao,1 Juan Chai,6 Xiangming Yang,1 Moyi Sun1

1State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China; 2Department of Stomatology, The First Hospital of Yu Lin, Yu Lin, Shaanxi, China; 3Department of Otolaryngology Head and Neck Surgery, Navy General Hospital, Beijing, China; 4Department of Geriatrics, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China; 5Department of Oral and Maxillofacial Surgery, General Hospital of Xinjiang Military Region, Urumqi, Xin Jiang, China; 6Department of Oral and Maxillofacial Surgery, School of Stomatology, Xi’an Medical University, Xi’an, Shaanxi, China

*These authors contributed equally to this work

Purpose: Perineural invasion (PNI) is reported to correlate with local recurrence and poor prognosis of salivary adenoid cystic carcinoma (SACC). However, the pathogenesis of PNI remains unclear. The aims of this study were to investigate the correlation between sympathetic innervation and SACC PNI and to elucidate how the sympathetic neurotransmitter norepinephrine (NE) regulates the PNI process.
Materials and methods: Sympathetic innervation and β2-adrenergic receptor (β2-AR) expression in SACC tissues were evaluated by immunohistochemistry. The NE concentrations in SACC tissues and dorsal root ganglia (DRG) coculture models were measured by ELISA. β2-AR expression in SACC cells was detected by performing quantitative real-time polymerase chain reaction (qRT-PCR) and immunofluorescence assay. SACC cells were treated with NE, the nonselective α-AR blocker phentolamine, the β2-AR antagonist ICI118,551, or were transfected with β2-AR small interfering RNA (siRNA). Proliferation was evaluated in methyl thiazolyl tetrazolium assay, and migration was evaluated in Transwell assay and wound-healing assay. PNI was tested through both Transwell assay and a DRG coculture model. The expressions of epithelial–mesenchymal transition (EMT) markers and matrix metalloproteinases (MMPs) were measured by performing qRT-PCR and Western blot assay.
Results: Sympathetic innervation and β2-AR were highly distributed in SACC tissues and correlated positively with PNI (P=0.035 and P=0.003, respectively). The sympathetic neurotransmitter NE was overexpressed in SACC tissues and DRG coculture models. Exogenously added NE promoted proliferation, migration, and PNI of SACC cells via β2-AR activation. NE/β2-AR signaling may promote proliferation, migration, and PNI by inducing EMT and upregulating MMPs. However, β2-AR inhibition with either an antagonist or siRNA abrogated NE-induced PNI.
Conclusion: Collectively, our findings reveal the supportive role of sympathetic innervation in the pathogenesis of SACC PNI and suggest β2-AR as a potential therapeutic target for treating PNI in SACC.

Keywords: salivary adenoid cystic carcinoma, perineural invasion, sympathetic innervation, β2-adrenergic receptor, norepinephrine

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