施万细胞旁分泌L1CAM嗜异性黏附Integrinα5介导食管癌嗜神经浸润的机制研究

Perineural invasion has been demonstrated as a new type of ESCC metastasis, which was associated with poor prognosis. Schwann cells are important part of the peripheral nerve. It is proved that Schwann cell promote cancer invasion in the perineural invasion, but its molecular mechanism is still unclear. In our previous work, we discovered that NGF secreted by ESCC cells promoted neurogenesis via Schwann cells. Schwann cells dedifferentiate to immature cells and re-express L1CAM, which expression was associated with perineural invasion in ESCC. We found that Integrin α5 was high expression in ESCC. Paracrine L1CAM by Schwann cells can activate the Integrin α5, and then significantly regulated the function of ERK1/2. As reported in the literature, ERK1/2 regulated the expression of E-cadherin, which played critical roles in the perineural invasion. These results imply that L1CAM secreted by dedifferentiated Schwann cells may heterotypic adhesion with Integrinα5 as a form of ERK1/2/E-cadherin pathway in perineural invasion of ESCC. Based on our previous work, we plan to investigate the role of Schwann cell in perineural invasion. We hope that the current study will provide novel insights into the cellar and molecular mechanism of perineural invasion in ESCC.

嗜神经浸润是食管癌转移新途径，提示患者预后不良。施万细胞是外周神经重要组成部分，研究证实参与肿瘤细胞的嗜神经浸润，但其分子机制尚不清楚。申请者前期研究发现，食管癌细胞旁分泌NGF吸引施万细胞促进神经新生；食管癌组织中的施万细胞发生去分化并高表达L1CAM蛋白，其表达水平与嗜神经浸润密切相关；Integrinα5在食管癌细胞高表达；施万细胞旁分泌L1CAM可激活Integrinα5显著调控ERK1/2的功能；根据文献报道，ERK1/2可调控E-cadherin表达，而E-cadherin是肿瘤嗜神经浸润的关键分子。据此我们推测：去分化的施万细胞旁分泌L1CAM嗜异性黏附食管癌细胞integrinα5调控ERK1/2/E-cadherin信号通路是食管癌嗜神经浸润的新机制。本项目拟在前期研究基础上，探讨施万细胞在食管癌嗜神经浸润中的作用，为深入理解嗜神经浸润发生机制提供新的实验室证据。

嗜神经浸润是食管癌转移新途径，提示患者预后不良。施万细胞是外周神经重要组成部分，研究证实其不仅在维持神经元的存活、引导轴突再生及促进神经损伤后修复等过程中扮演重要角色，还参与肿瘤细胞的嗜神经浸润，但其分子机制尚不清楚。我们前期研究发现，食管癌组织中的施万细胞发生去分化并高表达L1CAM蛋白，其表达水平与嗜神经浸润密切相关，为研究其在嗜神经浸润中发挥分子机制，我们进行了深入研究。我们研究证实：1.食管癌嗜神经浸润存在及意义。2.施万细胞在体内、外发生去分化。3.施万细胞旁分泌L1CAM黏附Integrin α5影响食管癌嗜神经浸润。4. L1CAM/Integrin α5/E-cadherin调控食管癌嗜神经浸润的水平。据此我们证实：去分化的施万细胞旁分泌L1CAM嗜异性黏附食管癌细胞integrin α5调控ERK1/2/E-cadherin信号通路是食管癌嗜神经浸润的新机制。本项目在前期研究基础上，探讨了施万细胞在食管癌嗜神经浸润中的作用，为深入理解嗜神经浸润发生机制提供新的实验室证据。