EMMPRIN和BDNF/TrkB协同调控EMT促进涎腺腺样囊性癌嗜神经侵袭的机制研究

The perineural invasion of salivary adenoid cystic carcinoma (SACC) results in serious damage to the patients, while the mechnism of perineural invasion is still illusive. Our previous studies found that EMMPRIN together with BDNF and BDNF' receptor (TrkB) mutually regulated the perineural invasion of SACC. We further invesigate the perineural invasion mechnism of SACC in the present study. Firstly, we hypothesize and test the new perineural invasion mechnism of which EMMPRIN and BDNF/TrkB inducing the epithelial-mesenchymal transition (EMT) by analyzing the expression of EMMPRIN, BDNF, TrkB, and EMT related molecules in clinical specimens, SACC cells and neural cells co-culture models, and three dimensional culture models. Secondly, we purpose to clarify the signalling channel involved in the EMMPRIN and BDNF/TrkB induced EMT via series tests such as RNAi, PCR, Western Blot and so on. Finally, we aim to discusses the mechnism and therapeutic effect of silencing of EMMPRIN and TrkB on SACC cells both in in vitro and in vivo perineural invasion models. This study will not only clarify the mechanism of perineural invasion, but also provide new strategy and potent target for the genetherapy of SACC.

嗜神经侵袭是涎腺腺样囊性癌(SACC)对机体造成巨大伤害的主要原因之一，但其发生机制仍未确切阐明。我们前期研究发现EMMPRIN与BDNF及其受体TrkB在SACC与神经间形成分子信号反馈回路，协同促进SACC 的嗜神经侵袭。本项目进一步深入研究SACC 嗜神经侵袭的机制。首先通过分析SACC嗜神经侵袭标本、SACC和神经细胞共培养及3D培养模型中EMMPRIN、BDNF、TrkB及上皮间质转化(EMT)相关分子的表达，初步验证EMMPRIN和BDNF/TrkB 协同调控EMT促进SACC嗜神经侵袭的机制假说。然后通过RNAi、PCR、WB等方法明确EMMPRIN和BDNF/TrkB协同调控EMT的具体信号通路。最后通过体外和体内嗜神经侵袭模型探讨联合沉默EMMPRIN和TrkB抑制SACC嗜神经侵袭的治疗前景。该项目不仅丰富了SACC嗜神经侵袭的机制，也为其基因治疗提供了新策略和新靶点。

涎腺腺样囊性癌(SACC)具有嗜神经侵袭的特性，是其对机体造成巨大伤害的主要原因之一，但其发生机制仍未确切阐明。我们前期研究发现EMMPRIN 与BDNF 及其受体TrkB 在SACC 与神经间形成分子信号反馈回路，协同促进SACC 的嗜神经侵袭。本项目进一步深入研究了SACC 嗜神经侵袭的潜在机制。首先通过分析SACC 嗜神经侵袭标本、SACC 和神经细胞共培养及3D 培养模型中EMMPRIN、BDNF、TrkB 及上皮间质转化(EMT)相关分子的表达，初步验证了EMMPRIN 和BDNF/TrkB 协同调控EMT 促进SACC 嗜神经侵袭的机制假说。然后通过RNAi、PCR、WB 等方法明确EMMPRIN 和BDNF/TrkB 协同调控EMT 的部分分子信号通路。最后通过体外和体内嗜神经侵袭模型探讨了联合沉默EMMPRIN 和TrkB 抑制SACC 嗜神经侵袭的治疗前景。该项目不仅丰富了SACC 嗜神经侵袭的机制，也为其基因治疗提供了新靶点和新策略。