Wei Xiaoyong, Zou Long, Huang Yanqing, Qiu Chuan, Cheng Guang, Chen Ye, Rao Jun
Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Hospital, Jiangxi Clinical Research Center for Cancer, Nanchang, Jiangxi, 330029, China.
The Medical College of Nanchang University, Nanchang, Jiangxi, 330006, China.
Biol Direct. 2025 May 26;20(1):64. doi: 10.1186/s13062-025-00655-6.
Hepatocellular carcinoma (HCC) is among the deadliest cancers globally. Yes-Associated Protein (YAP), a Hippo pathway effector, crucially regulates cell proliferation and apoptosis. Recent research has implicated YAP's role in HCC progression, but the mechanisms are unclear. This study aims to clarify YAP's function in HCC, emphasizing its regulation of key pathways and targets.
Gene knockout and overexpression models were established in nude mice and cell lines of HCC cells to investigate YAP's impact on tumorigenesis. Additionally, functional assays and molecular biology techniques were employed to identify YAP's regulatory networks. The study demonstrates that LDHA-regulated lactate production promotes YAP activation and malignant phenotypes in HCC. Overexpression of LDHA in HepG2 and Huh7 cells increased lactate levels and activated the YAP pathway, enhancing cell proliferation, migration, and invasion. Lactate treatment also promoted these malignant phenotypes by inhibiting YAP phosphorylation at Ser127. In a xenograft model, lactate accelerated tumor growth through YAP activation. YAP lactylation at K102 antagonized its Ser127 phosphorylation, further promoting malignant progression.
This study highlights the significance of YAP in HCC pathogenesis, providing insights into potential therapeutic targets for HCC management.
肝细胞癌（HCC）是全球最致命的癌症之一。Yes相关蛋白（YAP）作为一种Hippo信号通路效应因子，对细胞增殖和凋亡起着关键的调节作用。最近的研究表明YAP在HCC进展中发挥作用，但其机制尚不清楚。本研究旨在阐明YAP在HCC中的功能，重点关注其对关键信号通路和靶点的调控。
在裸鼠和HCC细胞系中建立基因敲除和过表达模型，以研究YAP对肿瘤发生的影响。此外，采用功能分析和分子生物学技术来确定YAP的调控网络。研究表明，LDHA调节的乳酸生成促进了HCC中YAP的激活和恶性表型。HepG2和Huh7细胞中LDHA的过表达增加了乳酸水平并激活了YAP信号通路，增强了细胞增殖、迁移和侵袭能力。乳酸处理也通过抑制YAP在Ser127位点的磷酸化促进了这些恶性表型。在异种移植模型中，乳酸通过激活YAP加速了肿瘤生长。YAP在K102位点的乳酸化拮抗了其Ser127位点的磷酸化，进一步促进了恶性进展。
本研究强调了YAP在HCC发病机制中的重要性，为HCC治疗的潜在靶点提供了见解。
