Recent Advances of the Wiskott-aldrich Syndrome Protein Family Members in Tumorigenesis and Progression

doi:10.12114/j.issn.1007-9572.2021.01.029

Chinese General Practice ›› 2022, Vol. 25 ›› Issue (14): 1779-1789.DOI: 10.12114/j.issn.1007-9572.2021.01.029

Special Issue: 肿瘤最新文章合集

• Review • Previous Articles Next Articles

Recent Advances of the Wiskott-aldrich Syndrome Protein Family Members in Tumorigenesis and Progression

Affiliated Hospital of Zunyi Medical University/Hematology-Oncology Departmen of Guizhou Children's Hospital, Zunyi 563000, China

Received:2021-06-26 Revised:2021-09-19 Published:2022-03-24 Online:2022-04-07
Contact: Zhixu HE
About author:
XIE X, CHEN Y, HE Z X, et al. Recent advances of the Wiskott-Aldrich syndrome protein family members in tumorigenesis and progression[J]. Chinese General Practice, 2022, 25 (14) : 1779-1789.

WASP家族在肿瘤发生发展中作用的研究进展

563000　贵州省遵义市，遵义医科大学附属医院/贵州省儿童医院血液肿瘤科

通讯作者: 何志旭
作者简介:
谢馨，陈艳，何志旭，等. WASP家族在肿瘤发生发展中作用的研究进展[J].中国全科医学，2022，25（14）：1779-1789. [www.chinagp.net] 作者贡献：谢馨负责选题、文章的构思和设计，文献资料收集与整理，撰写及修改论文，制作图表；黄佩负责选题，文章构思和设计，修改论文和图表；陈青华参与文献资料收集与整理；陈艳参与文章的构思和设计，文章初稿的修改；何志旭负责选题、文章的构思与设计、文章修改和监督管理，对文章整体负责。
基金资助:
国家自然科学基金资助项目(82060675); 贵州省科技计划项目(黔科合基础20201Y313); 遵义医科大学学术新苗及创新探索专项(黔科合平台人才2017-5733-004); 遵义医科大学附属医院科研启动基金(院字2018-09)

Abstract

Abstract:

The development of cancer is an evolving process, with proliferation, invasion and metastasis as basic biological features. As a new class of actin regulatory proteins, Wiskott-aldrich syndrome protein (WASP) family is a key component in maintaining the basic morphology of actin cytoskeleton that is involved in many essential processes including maintaining basic structure of cells, and cell motility and signaling. It also mediates the proliferation, invasion and metastasis of cancer cells. We reviewed latest advances in the role of WASP family in cancer formation and progression, its expression levels in different cancers and related signaling pathways, suggesting that relevant research is highly promising, and reflecting the importance of WASP family in mechanisms of carcinogenesis, cancer treatment and prognosis prediction.

Key words: WASP family, Wiskott-aldrich syndrome protein family, Neoplasms, Invasion, Neoplasm metastasis, Review

摘要：

恶性肿瘤的发生、发展是一个不断演进的过程，其具有侵袭、浸润和转移的基本生物学特征。WASP家族作为一类新型的肌动蛋白调节蛋白，是参与维持肌动蛋白细胞骨架的基本形态的关键成分，在维持细胞基础结构、细胞运动、细胞信号传导等在内的各种细胞过程中发挥着重要作用，同时也可介导肿瘤细胞的增殖、侵袭和转移。本文综述了WASP家族在肿瘤发生、发展中的作用，以及在不同肿瘤中的表达情况及其相关信号通路，提示WASP家族在肿瘤的发生及进展中存在广阔的研究空间，对于WASP家族在各种肿瘤中的机制研究、预后预测、甚至治疗等方面均有着重要意义。

关键词: WASP家族, Wiskott-Aldrich综合征蛋白质家族, 肿瘤, 侵袭, 肿瘤转移, 综述

Xin XIE,Yan CHEN,Zhixu HE, et al. Recent Advances of the Wiskott-aldrich Syndrome Protein Family Members in Tumorigenesis and Progression[J]. Chinese General Practice, 2022, 25(14): 1779-1789. DOI: 10.12114/j.issn.1007-9572.2021.01.029.
谢馨,陈艳,何志旭等. WASP家族在肿瘤发生发展中作用的研究进展[J]. 中国全科医学, 2022, 25(14): 1779-1789. DOI: 10.12114/j.issn.1007-9572.2021.01.029.

Figures/Tables 4

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WASP家族	特殊生理作用	共同生理作用
WASP	细胞毒性^[4]	促进肌动蛋白聚合^[8] 调节细胞骨架、维持细胞基础结构^[8] 细胞迁移、运动^[10] 促进侵袭性伪足形成^[10]
	受体信号传导^[7]
	促进淋巴细胞和髓细胞迁移^[11]
	T淋巴细胞的免疫突触形成^[12，13]
	单核细胞的吞噬^[11]
N-WASP	调节肠上皮分化^[14]
	维持正常组织结构的完整性^[14]
	调节成肌细胞与细胞之间的融合^[15]
	调节少突细胞髓鞘形成^[16]
	宿主-病原体相互作用^[17]
	寄生虫感染^[17]
	基质重塑过程^[18]
	血管内皮细胞迁移及血管新生^[19]
WHAMY	维持高尔基体结构^[20]
	维持胞内物质运输过程^[20]
	促进细胞自噬体形成^[9]
	细胞减数分裂过程^[21]
WASH	细胞减数分裂过程^[22]
YMY	影响血睾屏障功能^[23]
	干扰精子发生过程^[23]

WASP家族	特殊生理作用	共同生理作用
WASP	细胞毒性^[4]	促进肌动蛋白聚合^[8] 调节细胞骨架、维持细胞基础结构^[8] 细胞迁移、运动^[10] 促进侵袭性伪足形成^[10]
	受体信号传导^[7]
	促进淋巴细胞和髓细胞迁移^[11]
	T淋巴细胞的免疫突触形成^[12，13]
	单核细胞的吞噬^[11]
N-WASP	调节肠上皮分化^[14]
	维持正常组织结构的完整性^[14]
	调节成肌细胞与细胞之间的融合^[15]
	调节少突细胞髓鞘形成^[16]
	宿主-病原体相互作用^[17]
	寄生虫感染^[17]
	基质重塑过程^[18]
	血管内皮细胞迁移及血管新生^[19]
WHAMY	维持高尔基体结构^[20]
	维持胞内物质运输过程^[20]
	促进细胞自噬体形成^[9]
	细胞减数分裂过程^[21]
WASH	细胞减数分裂过程^[22]
YMY	影响血睾屏障功能^[23]
	干扰精子发生过程^[23]

作用	机制
参与细胞黏附	激活Arp2/3复合物，促进肌动蛋白结构形成^[23]
参与细胞黏附	WasC通过阻断VCA结构域的活性抑制F-肌动蛋白聚合从而抑制细胞之间的黏附作用^[24]
降解细胞外基质	WAVE3激活NFκB通路和MAPK信号通路，从而激活基质金属蛋白酶MMP^[26]
促进血管新生	WASP重组细胞骨架，促进血管内皮细胞移行^[29]
促进血管新生	WASP通过激活MMP，启动内皮细胞的激活和迁移，稳定新生血管^[27]
	N-WASP磷酸化从而促进血管内皮细胞迁移及血管新生^[30]
促进细胞运动	N-WASP在甲状腺激素刺激下，激活FAK/paxillin/cortactin/N-WASP/Arp2/3复合信号通路，增强细胞运动能力^[33]
	肌动球蛋白介导的细胞收缩为细胞体向前运动提供能量，为胞体前缘产生收缩力，从而促进胞体与基质分离^[31]
促进形成侵袭性伪足	在Rac和Cdc42调节下，促进质膜突起形成层状伪足和丝状伪足^[36，37]
参与肿瘤免疫	参与免疫突触的形成和T淋巴细胞发育^[39，40]
	调节BCR信号通路和抗原内化提呈过程^[41，42]
	影响巨噬细胞的趋化作用和吞噬作用^[44]
	N-WASP通过NF-κB和MAPK的信号通路，影响炎性因子表达水平^[45]
参与肿瘤代谢	与TRIM21形成螯合物，从而保持PFK的活性，促进糖酵解过程^[47]
参与肿瘤代谢	通过Rac1/ROS信号通路促进活性氧（ROS）的生成^[49]
参与肿瘤死亡	WAVE3激活AKT促存活信号通路，加强肿瘤细胞对凋亡信号和TNF-α介导的细胞死亡信号的敏感性，从而促进肿瘤细胞的凋亡和死亡^[50]
	WAVE2通过Rac1/ROS信号通路促进活性氧（ROS）生成^[49]
	WASP缺陷时，在CD24交联诱导下使细胞凋亡增强^[51]
	促进自噬小体形成^[52]
参与肿瘤耐药	通过Beclin1/Bcl-2和Beclin1/PI3K-Ⅲ复合物途径增强白血病细胞的存活和调节化疗耐药^[53]

作用	机制
参与细胞黏附	激活Arp2/3复合物，促进肌动蛋白结构形成^[23]
参与细胞黏附	WasC通过阻断VCA结构域的活性抑制F-肌动蛋白聚合从而抑制细胞之间的黏附作用^[24]
降解细胞外基质	WAVE3激活NFκB通路和MAPK信号通路，从而激活基质金属蛋白酶MMP^[26]
促进血管新生	WASP重组细胞骨架，促进血管内皮细胞移行^[29]
促进血管新生	WASP通过激活MMP，启动内皮细胞的激活和迁移，稳定新生血管^[27]
	N-WASP磷酸化从而促进血管内皮细胞迁移及血管新生^[30]
促进细胞运动	N-WASP在甲状腺激素刺激下，激活FAK/paxillin/cortactin/N-WASP/Arp2/3复合信号通路，增强细胞运动能力^[33]
	肌动球蛋白介导的细胞收缩为细胞体向前运动提供能量，为胞体前缘产生收缩力，从而促进胞体与基质分离^[31]
促进形成侵袭性伪足	在Rac和Cdc42调节下，促进质膜突起形成层状伪足和丝状伪足^[36，37]
参与肿瘤免疫	参与免疫突触的形成和T淋巴细胞发育^[39，40]
	调节BCR信号通路和抗原内化提呈过程^[41，42]
	影响巨噬细胞的趋化作用和吞噬作用^[44]
	N-WASP通过NF-κB和MAPK的信号通路，影响炎性因子表达水平^[45]
参与肿瘤代谢	与TRIM21形成螯合物，从而保持PFK的活性，促进糖酵解过程^[47]
参与肿瘤代谢	通过Rac1/ROS信号通路促进活性氧（ROS）的生成^[49]
参与肿瘤死亡	WAVE3激活AKT促存活信号通路，加强肿瘤细胞对凋亡信号和TNF-α介导的细胞死亡信号的敏感性，从而促进肿瘤细胞的凋亡和死亡^[50]
	WAVE2通过Rac1/ROS信号通路促进活性氧（ROS）生成^[49]
	WASP缺陷时，在CD24交联诱导下使细胞凋亡增强^[51]
	促进自噬小体形成^[52]
参与肿瘤耐药	通过Beclin1/Bcl-2和Beclin1/PI3K-Ⅲ复合物途径增强白血病细胞的存活和调节化疗耐药^[53]

	肿瘤	WASP家族	表达	机制	预后作用	通路
血液系统	CML	WASP	随CML的进展而降低，与BCR-ABL1的表达呈负相关^[53]	不明	不良预后^[53]	不明
	JMML	WAS基因突变	下降^[54]	不明	不详	可能与RAS通路活化相关^[54]
	淋巴瘤	WASP选择性下降^[55]	下降^[55]	WASP蛋白缺陷时，CDC42与GTP结合增加，激活下游STAT3和MAPK通路，加速T淋巴瘤的病程^[56]	不良预后^[56]	STAT3通路、换行MAPK通路^[56]
消化系统	肝细胞癌	N-WASP	升高^[57]	作为细胞骨架调节因子，促进肿瘤细胞侵袭和转移^[9]	不良预后^[57]	不明
消化系统		WAVE2	升高^[58]	作为细胞骨架调节因子，促进肿瘤细胞侵袭和转移^[9]	不良预后^[58]	不明
	肝内胆管细胞癌	WAVE3	升高^[59]	诱导上皮-间充质转化^[59]，增强癌细胞的迁移和侵袭能力	不良预后^[59]	不明
	胰腺导管细胞癌	WAVE3	升高^[60]	抑制PDK2的表达，抑制AKT通路中Ser473的磷酸化，从而影响蛋白激酶B（PBK/AKT）通路，影响AKT途径下游蛋白如EMT相关蛋白、p53、Bcl-2和cyclin D1的表达，影响细胞增殖、迁移和侵袭^[60]	不良预后^[61]	AKT途径^[60]
		N-WASP	升高^[60]	通过p120-catenin/β-catenin/p21通路，在胰腺导管细胞癌中发挥致癌作用^[62]；此外N-WASP也是胰腺癌细胞上皮-间质转化的调节因子，可促进胰腺癌细胞的远处转移^[63]	不良预后^[61]	p120-catenin/β-catenin/p21通路^[62，63]
	大肠癌	WASP	低表达甚至无表达^[64]	不详	不详	不详
		N-WASP	升高^[64]	肌动蛋白骨架机制^[13]，促进淋巴结转移、炎性反应、肿瘤细胞转移、侵袭和肿瘤出芽^[64]	不良预后^[64]	不详
	食管癌	WAVE3	升高^[66]	肌动蛋白骨架机制^[66]	不良预后^[66]	不详
		WASH	升高^[67]	WASH在miR-637作用下表达上调，进而上调CXCL8，促进食管鳞癌细胞的干性，促进癌细胞的生长及转移^[67]	不良预后^[67]	不详
		N-WASP	升高^[65]	肌动蛋白骨架机制^[65]	不良预后^[65]	不详
生殖系统	乳腺癌	WASP	下降^[68]	WASP的缺陷会影响集落刺激因子对巨噬细胞的趋化作用，从而打断巨噬细胞与乳腺癌细胞之间的作用，使肿瘤细胞恶性增殖，促进癌细胞的运动、侵袭、内渗及转移^[69]	不良预后^[68]	不详
		N-WASP	下降^[70]	肌动蛋白骨架机制^[13]	不良预后^[71]	不详
		WAVE2^[72]	升高^[72]	通过Rac1-WAVE信号通路促进侵袭性板足形成，从而促进肿瘤细胞的侵袭和迁移能力^[72]	不良预后^[72]	Rac1-WAVE信号通路^[72]
	卵巢癌	WAVE	升高^[75]	肌动蛋白骨架机制^[13]	不良预后^[75]	不详
	前列腺癌	WAVE1	升高^[78]	肌动蛋白骨架机制，促进运动、侵袭和转移^[78]	不良预后^[78]	不详
		WAVE3	升高^[79]	肌动蛋白骨架机制，促进运动、侵袭和转移^[79]	不良预后^[79]	不详
		WASP	升高^[80]	WASP可接收Rho-GTPase家族的上游信号，将信号传递给Arp2/3复合体，从而导致细胞前缘肌动蛋白的快速聚合，促进侵袭性伪足的形成从而促进癌细胞转移^[80]	不良预后^[80]	不详
	宫颈癌	N-WASP^[77]	升高^[77]	N-WASP通过调节p38 MAPK通路的活性，参与肿瘤浸润与转移^[77]	不良预后^[77]	p38-MAPK通路^[77]
	子宫内膜癌	N-WASP	升高^[76]	在miR-216a-5p调控下表达上调，从而促进子宫内膜癌细胞的增殖、迁移和侵袭能力^[76]	不良预后^[76]	miR-216a-5p调控^[76]
泌尿系统	肾癌	N-WASP	下降^[81]	SNHG14通过与转录因子SP1结合使其在癌组织中表达增强，并通过miR-203依赖的方式调节N-WASP蛋白表达水平，从而促进肾脏肿瘤细胞迁移和侵袭的能力^[84]	表达升高时预示不良预后^[82，83]	不详
呼吸系统	肺癌	N-WASP	升高^[88]	N-WASP可与生长阻滞特异蛋白7（GAS7）结合，从而激活纤维连接蛋白/整合素/FAK通路（N-WASP/FAK/F-actin），促进细胞骨架动力学，增加癌细胞运动，促进肺癌转移^[88]	不良预后	纤维连接蛋白/整合素/FAK通路（N-WASP/FAK/F-actin）^[88]
	鼻咽癌	N-WASP	升高^[89]	在CDC42结合蛋白（CIP4）激活下，促进侵袭性伪足的形成，并激活EGFR信号，从而诱导下游MMP2（基质金属蛋白酶2）上调，促进鼻咽癌转移^[89]	不良预后^[89]	EGFR信号^[89]
中枢神经系统	神经胶质母细胞瘤	N-WASP	升高^[92]	N-WASP可参与室管膜细胞和神经元的迁移和突触调节^[90]，调节少突胶质细胞髓鞘和再髓鞘过程^[91]，参与肿瘤细胞的扩散、迁移和侵袭^[92]	不良预后^[92]	不详
其他系统	黑色素瘤	WAVE1\WAVE2	升高^[85，86]	WAVE1和WAVE2作为Rac下游的主要效应因子，通过激活Arp2/3复合物调节肌动蛋白细胞骨架，促进肿瘤细胞侵袭和转移^[85，86]	不良预后^[85，86]	Rac1-WAVE信号通路^[85，86]

Recent Advances of the Wiskott-aldrich Syndrome Protein Family Members in Tumorigenesis and Progression

WASP家族在肿瘤发生发展中作用的研究进展

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