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浙江大学学报（医学版）
浙江大学学报（医学版）  2020, Vol. 49 Issue (1): 82-89    DOI: 10.3785/j.issn.1008-9292.2020.02.08
综述     
内源性信号通路在神经元轴突再生中的功能和机制研究
王燚锋, 王志萍
浙江大学医学院神经科学研究中心 卫生部医学神经生物学重点实验室, 浙江 杭州 310058
Research progress on intrinsic signaling pathways in axon regeneration
WANG Yifeng, WANG Zhiping
NHC and CAMS Key Laboratory of Medical Neurobiology, Center for Neuroscience, Zhejiang University School of Medicine, Hangzhou 310058, China
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摘要：

神经元内源性再生能力是神经元再生和功能恢复的关键。近年研究发现了多个调控轴突再生的内源性信号通路，其中丝裂原活化蛋白激酶（MAPK）信号通路和磷脂酰肌醇3-激酶/蛋白激酶B（PI3K/Akt）信号通路最具代表性。MAPK信号通路参与轴突损伤的感知、再生的启动和维持等过程，通过调节蛋白合成和细胞骨架来调控轴突再生；PI3K/Akt信号通路则通过调节损伤后神经元内相关基因的转录和翻译调控轴突再生。多种再生促进信号的共同作用能进一步提升轴突再生能力。本文综述了MAPK和PI3K/Akt信号通路在不同模式生物中调控轴突再生的研究进展，并展望了其在促进体内神经功能恢复上的重要作用。

关键词： 神经再生/轴突;  有丝分裂素激活蛋白激酶类;  磷脂酰肌醇3-激酶;  信号传导;  综述    
Abstract:

The intrinsic regrowth ability of injured neurons is essential for axon regeneration and functional recovery. Recently, numerous intrinsic pathways that regulate axon regeneration have been discovered, among which the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway are arguably the best characterized examples. MAPK signaling pathway is involved in multiple processes including sensing injury signals, initiating and promoting axonal regrowth through regulating cytoskeleton dynamics and protein synthesis. The PI3K/Akt signaling pathway regulates axon regeneration mainly through gene transcription and translation. Combinatory manipulation of multiple regeneration-promoting signals can further improve the extend of axonal regrowth. This paper summarizes current progresses on axon regeneration studies in various organisms and discuss their potentials in promoting functional recovery in vivo.

Key words: Nerve regeneration/axons    Mitogen-activated protein kinases    Phosphatidylinositol 3-kinase    Signal transduction    Review
收稿日期: 2019-11-10 出版日期: 2020-06-30
CLC:  R741  
基金资助: 国家自然科学基金（31671039）
通讯作者: 王志萍      E-mail: z4wang@zju.edu.cn
作者简介: 王燚锋(1995-),男,硕士研究生,主要从事神经再生研究;E-mail:21718555@zju.edu.cn;https://orcid.org/0000-0002-8909-8213
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引用本文:

王燚锋, 王志萍. 内源性信号通路在神经元轴突再生中的功能和机制研究[J]. 浙江大学学报（医学版）, 2020, 49(1): 82-89.

WANG Yifeng, WANG Zhiping. Research progress on intrinsic signaling pathways in axon regeneration. J Zhejiang Univ (Med Sci), 2020, 49(1): 82-89.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2020.02.08    或    http://www.zjujournals.com/med/CN/Y2020/V49/I1/82

图 1  间充质干细胞向肿瘤组织靶向归巢可能的机制
肿瘤模型 肿瘤细胞系 肿瘤组织炎症因子 MSC来源 MSC上的相应受体 参考文献
“—”：无相关资料.CXCL:趋化因子CXC亚家族配体; CXCR:趋化因子CXC亚家族受体.
乳腺癌 SUM1315、MDA-MB-231 TGF-β1 人骨髓 — [39]
4T1 TGF-β1、血管内皮生长因子、血小板源生长因子BB 小鼠骨髓 CCR2 [40]
MDA-MB-231、MCF-7、MDA-MB-468 IL-6 人骨髓 — [41]
肝癌 SNU-398、Hep3B CXCL12 人骨髓 CXCR4 [37]
HuH7 巨噬细胞炎性蛋白1δ、巨噬细胞炎性蛋白3α、基质金属蛋白酶1 人骨髓 — [42]
HCCLM3 表皮细胞生长因子、CXCL9、CCL25、基质金属蛋白酶9 小鼠骨髓 — [25]
脑胶质瘤 U251 CXCL12 人脐带血 CXCR4 [38]
U87 IL-8 人脐带血 CXCR1 [43-44]
U87、U251、LN229 血小板源生长因子BB、表皮细胞生长因子、CXCL12 人骨髓 — [45]
前列腺癌 PC3、DU145 CXCL12 大鼠骨髓 CXCR4 [46]
PC3、LNCaP、DU145、RM1、Tramp CXCL16 人/小鼠骨髓 CXCR6 [47]
骨肉瘤 Saos-2 CXCL12 人骨髓 CXCR4 [19]
髓母细胞瘤 Daoy、D283 CXCL12 人脐带血 CXCR4 [48]
表 1  肿瘤细胞通过释放多种趋化因子吸引间充质干细胞(MSC)靶向归巢研究结果一览
治疗基因 基因重组载体 肿瘤类型 作用机制 参考文献
“—”：无相关资料；NK4:一种在胃癌中异常激活的肝细胞生长因子受体；HNF4α:肝细胞核因子4α；siIMPORTER:一种商品化转染试剂；Stat3:信号转导及转录激活因子3.
自杀基因
  单纯疱疹病毒胸苷激酶 精胺-普鲁兰多糖 黑色素肺转移瘤 表达前药活化酶，将无毒性的前药活化为DNA原料结构类似物，在杀伤间充质干细胞的同时通过旁观者效应杀伤肿瘤细胞 [33]
杆状病毒 脑胶质瘤 [75]
  胞嘧啶脱氢酶 腺病毒 脑胶质瘤 [76]
凋亡诱导蛋白
  肿瘤坏死因子相关细胞凋亡诱导配体 环糊精修饰的低分子量聚乙烯二胺 黑色素肺转移瘤 激活半胱氨酸蛋白酶8 [52]
逆转录病毒 乳腺癌、宫颈癌、胰腺癌、结肠癌 [77]
腺病毒 食道癌 [79]
逆转录病毒 尤因肉瘤 [80]
慢病毒 舌鳞状细胞癌 [81]
  Apoptin 慢病毒 肺癌 激活半胱氨酸蛋白酶3 [82]
腺病毒 肝癌 [83]
细胞因子和趋化因子
  IL-2 腺病毒 脑胶质瘤 — [84]
  IL-12 腺病毒 肾细胞癌 激活自然杀伤细胞和促进γ干扰素的分泌 [85]
慢病毒 恶性腹水瘤 吸引树突细胞趋化，刺激免疫反应 [86]
腺病毒 尤因肉瘤 — [87]
  IL-21 腺病毒 淋巴瘤 诱导全身性抗肿瘤免疫力 [88]
  IL-18 腺病毒 脑胶质瘤 增强T细胞浸润和长期的抗肿瘤免疫力 [89]
  β干扰素 慢病毒 乳腺癌 抑制Stat3信号激活，下调乳腺癌细胞中c-Myc和基质金属蛋白酶2表达水平 [90]
逆转录病毒 胰腺癌 — [91]
  α干扰素 腺病毒 黑色素肺转移瘤 — [92]
  γ干扰素 腺病毒 白血病 — [93]
  CX3CL1 腺病毒 结肠癌、黑色素肺转移瘤 活化免疫系统 [94]
肿瘤血管新生抑制因子
  NK4 慢病毒 胃癌 抑制肿瘤组织血管生成 [95]
  色素上皮衍生因子 腺病毒 肺癌 [96]
腺病毒 恶性腹水瘤 [97]
转录调节因子/miRNA
  HNF4α 慢病毒 肝癌 下调Wnt/β-catenin信号通路 [98]
  miR-124、miR-145 siIMPORTER (Millipore) 脑胶质瘤 调控基因表达 [99]
表 2  间充质干细胞靶向递送系统携载治疗基因应用于肿瘤治疗的研究结果一览
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