Yes相关蛋白参与肝细胞癌发生发展的作用机制

马丹阳; 刘江凯

doi:10.12449/JCH260630

Yes相关蛋白参与肝细胞癌发生发展的作用机制

DOI: 10.12449/JCH260630

马丹阳¹,
刘江凯^2, , ,

1.
河南中医药大学第一临床医学院，郑州 450000
2.
河南中医药大学第一附属医院脾胃肝胆科，郑州 450000

基金项目:

河南省中医药拔尖人才 (Yu Wei Zhong Yi Han （2021） No.15);

河南中医药大学“双一流”创建工程中医学学科项目 (HSRP-DFCTCM-2023-3-23)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：马丹阳负责设计论文框架，写作思路，起草论文；刘江凯负责论文修改，指导撰写文章并最后定稿。

详细信息

通信作者:
刘江凯， 13592553982@126.com （ORCID： 0000-0002-1529-5089）

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出版历程
- 收稿日期: 2025-10-21
- 录用日期: 2025-12-19
- 出版日期: 2026-06-25

Mechanism of action of Yes-associated protein in the development and progression of hepatocellular carcinoma

Danyang MA¹,
Jiangkai LIU^{2
, ,
,}

1.
The First Clinical Medical College of Henan University of Chinese Medicine，Zhengzhou 450000，China
2.
Spleen，Stomach and Hepatobiliary Department，The First Affiliated Hospital of Henan University of Chinese Medicine，Zhengzhou 450000，China

Research funding:

Top-Tier TCM Talents of Henan Province (Yu Wei Zhong Yi Han （2021） No.15);

TCM Discipline Project of the “Double First-Class” Initiative Construction at Henan University of Chinese Medicine (HSRP-DFCTCM-2023-3-23)

More Information

Corresponding author: LIU Jiangkai， 13592553982@126.com （ORCID： 0000-0002-1529-5089）

摘要

摘要: 肝细胞癌（HCC）全球高发且病死率高。尽管目前手术、靶向药及免疫治疗不断发展，但因肿瘤异质性强、易转移且耐药率高等特点，患者5年生存率仍未显著提升。因此，寻找新的治疗靶点成为当务之急。Yes相关蛋白（YAP）的异常激活是HCC细胞增殖、转移及免疫逃逸的核心枢纽。本文系统综述了YAP在HCC中活化的多重调控机制，包括Hippo通路失活、G蛋白偶联受体信号激活及细胞外基质机械应力改变等对其入核功能的促进作用；归纳了YAP与Wnt通路等非经典通路的协同串扰关系，以及其通过上调程序性死亡配体1重塑免疫微环境、助力肿瘤免疫逃逸的具体作用；评述了YAP-TEA结构域转录因子抑制剂及蛋白降解靶向嵌合体等新技术的发展，并指出YAP多重调控机制的交叉作用是导致肿瘤异质性和治疗耐药的重要原因，未来靶向YAP调控网络的新型抑制剂开发、联合治疗策略及分子标志物检测体系构建，或成为推动HCC精准治疗的重要方向。
- 癌，肝细胞 /
- Yes相关蛋白 /
- 信号传导 /
- 肿瘤微环境
Abstract: Hepatocellular carcinoma （HCC） is highly prevalent worldwide with a high mortality rate. Despite the continuous advances in current treatment methods such as surgery， targeted drugs， and immunotherapy， there is still a lack of significant improvement in the 5-year survival rate of patients due to strong tumor heterogeneity， high metastatic potential， and a high drug resistance rate. Therefore， it is urgently needed to identify new therapeutic targets. The aberrant activation of Yes-associated protein （YAP） is a pivotal hub for cell proliferation， metastasis， and immune evasion of HCC. This article systematically reviews the multiple regulatory mechanisms underlying YAP activation in HCC， including the promotion of YAP nuclear translocation by Hippo pathway inactivation， G protein-coupled receptor signal activation， and changes in mechanical stress of extracellular matrix. Meanwhile， it summarizes the synergistic crosstalk between YAP and non-classical pathways such as the Wnt pathway， as well as its specific role in remodeling the immune microenvironment and facilitating tumor immune escape by upregulating programmed death ligand 1. In addition， it reviews the development of new technologies such as YAP-TEAD inhibitors and proteolysis-targeting chimera and points out that interactions between the multiple regulatory mechanisms of YAP is a key contributor to tumor heterogeneity and therapeutic resistance. Future research should focus on developing novel inhibitors targeting the YAP regulatory network， designing combined therapy strategies， and establishing molecular biomarker detection systems， which may become pivotal directions for promoting precise treatment of HCC.
- Carcinoma， Hepatocellular /
- Yes-associated Proteins /
- Signal Transduction /
- Tumor Microenvironment

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注： YAP，Yes相关蛋白；AMOT，Motin家族成员血管动蛋白；STRIPAK，纹状蛋白相互作用磷酸酶-激酶复合物；PP2A，蛋白磷酸酶2A；GPCR，G蛋白偶联受体；β-catenin，β-联蛋白；EGFR，表皮生长因子受体；RAS，大鼠肉瘤病毒癌基因；RAF，丝氨酸/苏氨酸蛋白激酶；MAPK，丝裂原活化蛋白激酶；TGF-β，转化生长因子β；SMAD，SMAD蛋白家族；PD-L1，程序性细胞死亡配体1；CTGF，结缔组织生长因子；CYR61，富含半胱氨酸的血管生成诱导因子61；MST，哺乳动物不育系20样激酶；LATS，大肿瘤抑制激酶；RhoA，RAS同源基因家族成员A；ROCK，Rho相关卷曲螺旋形成蛋白激酶；GLUT1，葡萄糖转运蛋白1；Gln，谷氨酰胺；PI3K，磷脂肌醇3-激酶；Akt，蛋白激酶B；ERK，胞外信号调节激酶；miR-375，微小RNA-375；LncRNA，长链非编码RNA；MALAT1，肺腺癌转移相关转录本1；TEAD，TEA结构域转录因子；IL-1β，白细胞介素1β；CCL2，趋化因子配体2。

图 1 YAP活化的主要来源、串扰通路及其作用

Figure 1. Main sources， crosstalk pathways and biological functions of YAP activation

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表 1 YAP在HCC中具体调控机制及作用

Table 1. The specific regulatory mechanisms and roles of YAP in HCC

调控层面	关键因素	关键分子	YAP参与核心机制	作用
Hippo通路	上游调控因子与核心激酶模块	AMOT-p130	磷酸化：YAP磷酸化并滞留于细胞质中，减少CTGF、 CYR61等下游靶基因的激活^［11-12］	↓
		AMOT-p130	非磷酸化：增强YAP与TEAD结合能力，增加下游靶基因的激活^［13］	↑
		STRIPAK	通过PP2A介导MST1/2去磷酸化，抑制下游LATS1/2 的激活，导致YAP/TAZ磷酸化^［16-17］	↑
		AMPK	—	—
非Hippo通路	GPCR信号级联	Gα12/13、Gαq/11	通过LPA受体介导的细胞骨架重排抑制LATS，激活 YAP^［19］	—
	GPCR信号级联	NPFFR2	激活RhoA/ROCK信号通路，促使YAP核转位^［20］	↑
	代谢重塑	GLUT1	YAP间接激活JNK/p38 MAPK通路，上调GLUT1，增强有氧糖酵解^［23］	↑
		GLUT1	YAP直接激活并上调GLUT1，增强有氧糖酵解 ^［25］	↑
		Gln	—	—
	机械应力	ECM	YAP直接响应ECM机械应力，上调各种靶基因的表达^［31］	↑
	机械应力	ECM	ECM激活PI3K/Akt、MAPK/ERK等促癌通路，激活 YAP/TAZ^［31］	↑
	表观遗传	miR-375	靶向YAP mRNA的3'UTR，负向调控YAP的表达^［33］	↓
		miR-375	抑制YAP下游靶点CTGF mRNA的水平，干扰YAP信号输出^［33］	↓
		LncRNA MALAT1	吸附抑癌miR-375，解除miR-375对YAP1的转录抑制，促使YAP1表达上调^［35］	↑
交叉调控	Wnt/β-catenin	CTGF、CYR61	协同激活下游靶基因CTGF、CYR61等的表达^［37］	↑
	Wnt/β-catenin	TBX3、CTNNB1	通过TBX3-PLD1-YAP/TAZ轴抑制CTNNB1基因突变型HCC进展^［40］	↓
	EGFR/RAS/RAF/ MAPK	RAF、ERK/JNK	RAF抑制MST激酶的激活；ERK/JNK磷酸化Ajuba，抑制LATS激酶活性，阻止YAP/TAZ失活^［43-44］	↑
	EGFR/RAS/RAF/ MAPK	EGFR、AREG	YAP/TAZ与TEAD结合，上调EGFR配体AREG等，抑制Hippo-YAP通路^［43-44］	索拉非尼耐药
	TGF-β/SMAD	SMAD、CYR61	早期，SMAD与YAP/TEAD4形成复合物，协同刺激 CYR61基因转录^［45］	↓
	TGF-β/SMAD	SMAD2/3	晚期，SMAD2/3磷酸化上调YAP/TAZ表达，诱导 SNAIL、SLUG、N-cadherin等的表达^［46-47］	↑
微环境调控	YAP/PD-L1	PD-L1、T细胞	YAP直接结合PD-L1的启动子区域，激活IL-1β/CCL2 通路，招募M2型巨噬细胞和Th2细胞，最终导致CD8⁺T 细胞功能耗竭^［48-49］	免疫逃逸
微环境调控	YAP液-液相分离	PD-L1、T细胞	协同增强PD-L1的转录效率，驱动CTGF、CYR61等下游靶基因的高表达^［50-51］	免疫治疗耐药
注：“—”表示不明确；“↑”表示促癌；“↓”表示抑癌。YAP，Yes相关蛋白；GPCR，G蛋白偶联受体；Wnt/β-catenin，Wnt/β-联蛋白信号通路；EGFR，表皮生长因子受体；RAS，大鼠肉瘤病毒癌基因；RAF，丝氨酸/苏氨酸蛋白激酶；MAPK，丝裂原活化的蛋白质激酶；TGF-β，转化生长因子β；SMAD，SMAD蛋白家族；PD-L1，程序性细胞死亡配体1；AMOT，Motin家族成员血管动蛋白；STRIPAK，纹状蛋白相互作用磷酸酶-激酶复合物；AMPK，AMP活化的蛋白质激酶；Gα12/13，G蛋白α12/13亚基；Gαq/11，G蛋白αq/11亚基；NPFFR2，神经肽FF受体2；GLUT1，葡萄糖转运蛋白1；Gln，谷氨酰胺；ECM，细胞外基质；miR-375，微RNA-375；lncRNA，长链非编码RNA；MALAT1，肺腺癌转移相关转录本1；CTGF，结缔组织生长因子；CYR61，富含半胱氨酸的血管生成诱导因子61；SMAD2/3，Smad2/3蛋白；TBX3，T-box转录因子3；CTNNB1，连环蛋白β1；ERK，胞外信号调节激酶；JNK，c-Jun氨基末端激酶；AREG，双调蛋白；TEAD，TEA结构域转录因子；PP2A，蛋白磷酸酶2A；MST1/2，哺乳动物不育系20样激酶1/2；LATS1/2，大肿瘤抑制激酶1/2；TAZ，具有PDZ结合基序的转录共激活因子；LPA，溶血磷脂酸；RhoA，RAS同源基因家族成员A；ROCK，Rho相关卷曲螺旋形成蛋白激酶；PI3K，磷脂肌醇3-激酶；Akt，蛋白激酶B；UTR，非翻译区； PLD1，磷脂酶D1；HCC，肝细胞癌；Ajuba，Ajuba LIM蛋白；SNAIL，Snail锌指转录因子；SLUG，Slug锌指转录因子；N-cadherin，N-钙黏蛋白；IL-1β，白细胞介素1β；CCL2，趋化因子配体2。

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