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脑源性神经营养因子（BDNF）介导的酪氨酸激酶受体B（TrkB）激活促进了人涎腺腺样囊性癌的上皮-间质转化进程及不良预后。

BDNF mediated TrkB activation contributes to the EMT progression and the poor prognosis in human salivary adenoid cystic carcinoma.

作者信息

Jia Sen, Wang Weixi, Hu Zhiqiang, Shan Chun, Wang Lei, Wu Baolei, Yang Zihui, Yang Xinjie, Lei Delin

机构信息

State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.

State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China; No. 150 Hospital of PLA, Luoyang 471031, China.

出版信息

Oral Oncol. 2015 Jan;51(1):64-70. doi: 10.1016/j.oraloncology.2014.10.008. Epub 2014 Oct 24.

DOI:10.1016/j.oraloncology.2014.10.008

PMID:25456007

Abstract

BACKGROUND

The aim of the present study was to investigate whether the expression of Brain-Derived Neurotrophic Factor (BDNF) and its receptor Tropomyosin-related kinase B (TrkB) is correlated with the clinical progression of salivary adenoid cystic carcinoma (SACC) and whether the BDNF/TrkB axis is associated with the induction of epithelial-mesenchymal transition (EMT) in SACC cells.

METHOD

The expression of BDNF, TrkB, and E-cadherin (an EMT biomarker) in 76 primary SACC specimens and 20 normal salivary gland tissues was analyzed by immunohistochemistry. Additionally, the expression of BDNF, TrkB, and E-cadherin in SACC cell lines (SACC-83 and SACC-LM) was analyzed by RT-PCR and Western blotting. The biological role of the BDNF/TrkB axis in the EMT progression of SACC was evaluated after treatment with increased levels of BDNF and by inhibiting TrkB activity in SACC-83 cell line. The progression of SACC cells through EMT was assessed by RT-PCR, Western blotting, photography, migration and invasion assays.

RESULTS

Elevated expression of TrkB (92.1%) and BDNF (89.5%), and downregulated expression of E-cadherin (47.4%) was found in SACC specimens, which was significantly correlated with the invasion and metastasis in SACC (P<0.05). The high expression of TrkB and the low expression of E-cadherin was significantly correlated with the poor prognosis of SACC patients (P<0.05). The expression of TrkB was inversely correlated with the expression of E-cadherin in both SACC cases and cell lines (P<0.05). Increasing BDNF levels after treatment with exogenous recombinant human BDNF (rhBDNF) at 100 ng/ml significantly promoted the activation of TrKB and the progression of EMT in SACC cells. While obstruction of TrkB by its inhibitor, k252a (100 nM), significantly inhibited the EMT progression of SACC cells.

CONCLUSIONS

These results suggest that BDNF-mediated TrkB activation contributes to the EMT progression and the poor prognosis in SACC. The present study demonstrated that the BDNF/TrkB axis promotes the migration and invasion of SACC cells via EMT in vitro. Targeting the inactivation of the BDNF/TrkB axis may be a potential strategy for the treatment of SACC.

摘要

背景

本研究旨在探讨脑源性神经营养因子（BDNF）及其受体原肌球蛋白相关激酶B（TrkB）的表达是否与涎腺腺样囊性癌（SACC）的临床进展相关，以及BDNF/TrkB轴是否与SACC细胞上皮-间质转化（EMT）的诱导有关。

方法

采用免疫组织化学法分析76例原发性SACC标本和20例正常涎腺组织中BDNF、TrkB和E-钙黏蛋白（一种EMT生物标志物）的表达。此外，采用逆转录-聚合酶链反应（RT-PCR）和蛋白质免疫印迹法分析SACC细胞系（SACC-83和SACC-LM）中BDNF、TrkB和E-钙黏蛋白的表达。在用增加水平的BDNF处理并抑制SACC-83细胞系中TrkB活性后，评估BDNF/TrkB轴在SACC的EMT进展中的生物学作用。通过RT-PCR、蛋白质免疫印迹法、摄影、迁移和侵袭试验评估SACC细胞通过EMT的进展。

结果

在SACC标本中发现TrkB（92.1%）和BDNF（89.5%）表达升高，E-钙黏蛋白表达下调（47.4%），这与SACC的侵袭和转移显著相关（P<0.05）。TrkB的高表达和E-钙黏蛋白的低表达与SACC患者的不良预后显著相关（P<0.05）。在SACC病例和细胞系中，TrkB的表达与E-钙黏蛋白的表达呈负相关（P<0.05）。用100 ng/ml的外源性重组人BDNF（rhBDNF）处理后增加BDNF水平，显著促进了TrKB的激活和SACC细胞中EMT的进展。而其抑制剂k252a（100 nM）阻断TrkB，显著抑制了SACC细胞的EMT进展。