靶向<italic style="font-style: italic">WTAP</italic>通过抑制ERK信号通路增强肝细胞癌对索拉非尼治疗的敏感性

吴俣; 琚国民; 周雪羽; 吴健; 郑树森; 彭传会

doi:10.1631/jzus.B2500191

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靶向WTAP通过抑制ERK信号通路增强肝细胞癌对索拉非尼治疗的敏感性

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Research Article | Updated：2026-03-18

靶向WTAP通过抑制ERK信号通路增强肝细胞癌对索拉非尼治疗的敏感性
Targeting WTAP sensitizes hepatocellular carcinoma to sorafenib by inhibiting the ERK signaling pathway
浙江大学学报（英文版）（B辑：生物医学和生物技术） 2026年27卷第3期页码：310-320
Affiliations：

1.Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
2.NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
3.Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
4.State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou 310003, China
5.Department of Thyroid Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
Funds：

the National Natural Science Foundation of China(82002925);the Department of Science and Technology of Zhejiang Province, China(2023C03063)
DOI：10.1631/jzus.B2500191
中图分类号：
CSTR：
收稿：2025-04-16，

修回：2025-06-25，

纸质出版：2026-03-18
Accepted：

吴俣,琚国民,周雪羽等.靶向WTAP通过抑制ERK信号通路增强肝细胞癌对索拉非尼治疗的敏感性[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2026,27(03):310-320.

Yu WU, Guomin JU, Xueyu ZHOU, et al. Targeting WTAP sensitizes hepatocellular carcinoma to sorafenib by inhibiting the ERK signaling pathway[J]. Journal of Zhejiang University-SCIENCE B, 2026, 27(3): 310-320.
吴俣,琚国民,周雪羽等.靶向WTAP通过抑制ERK信号通路增强肝细胞癌对索拉非尼治疗的敏感性[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2026,27(03):310-320. DOI： 10.1631/jzus.B2500191.

Yu WU, Guomin JU, Xueyu ZHOU, et al. Targeting WTAP sensitizes hepatocellular carcinoma to sorafenib by inhibiting the ERK signaling pathway[J]. Journal of Zhejiang University-SCIENCE B, 2026, 27(3): 310-320. DOI： 10.1631/jzus.B2500191.

摘要

肝细胞癌（HCC）确诊时常已进展至中晚期，因此需要进行靶向治疗和免疫治疗。索拉非尼作为HCC首个靶向药物，虽然具有一定疗效，但其临床应用常因耐药性发生及机制不明而受限。Wilms瘤1相关蛋白（WTAP）虽与肿瘤进展相关，但其在索拉非尼耐药中的作用尚未明确。本研究通过整合癌症基因组图谱（TCGA）数据和空间转录组学分析，系统解析了

WTAP

在HCC中的表达特征。我们综合采用基因集富集分析（GSEA）、R语言分析、体外实验、分子对接及蛋白质印迹分析等多维度方法，探究了

WTAP

介导索拉非尼耐药的潜在机制，并进一步通过尾静脉高压水动力注射小鼠模型和免疫组化实验验证

WTAP

在耐药中的作用。结果发现，HCC组织中

WTAP

显著上调，且与肿瘤进展和不良预后密切相关。此外，

体外敲低

WTAP

可增强HCC细胞对索拉非尼的敏感性。GSEA、分子对接及蛋白质印迹分析结果表明，

WTAP

通过激活ERK信号通路（耐药关键调控通路）诱导耐药形成。在小鼠肝癌模型中，联合

WTAP

敲低与索拉非尼治疗可显著抑制肿瘤生长并提高生存率。综上，本研究首次阐明

WTAP

通过正向调控ERK通路促进HCC索拉非尼耐药，提示靶向

WTAP

有望成为增强索拉非尼疗效的潜在新策略。

Abstract

Hepatocellular carcinoma (HCC) often requires targeted therapy and immunotherapy due to frequent delayed diagnosis. Sorafenib

the first targeted drug applied to treat HCC

has demonstrated a remarkable therapeutic effect in the clinic. However

its clinical application has been limited by drug resistance and the insufficient understanding of the relevant mechanism. Wilms’ tumor 1-associated protein (WTAP)

associated with tumor progression

remains unstated in sorafenib resistance. I

n this study

WTAP

expression patterns in HCC were systematically characterized through integrative analysis of The Cancer Genome Atlas (TCGA) datasets and spatial transcriptomic profiling. To delineate the potential mechanisms of

WTAP

-mediated sorafenib resistance in HCC

multimodal approaches integrating gene set enrichment analysis (GSEA)

predictions from the “oncoPredict” package in vitro experiments

molecular docking simulations

and western blot validation were applied. To further investigate the role of

WTAP

in drug resistance

hydrodynamic tail vein injection (HTVi) mouse models and immunohistochemistry were utilized. Significant

WTAP

upregulation was identified in HCC tissues

showing strong associations with tumor progression and adverse clinical outcomes. The knockdown of

WTAP

sensitized HCC cells to sorafenib in vitro. GSEA

molecular docking analysis

and western blot analysis demonstrated that

WTAP

induces the activation of the extracellular signal-regulated kinase (ERK) signaling pathway

a critical link in chemoresistance mechanisms. In the HTVi HCC model

the combination of

WTAP

knockdown with sorafenib markedly suppressed tumor progression and boosted survival rates. These findings highlight that

WTAP

positively regulates the ERK pathway in HCC

promoting sorafenib resistance; therefore

targeting

WTAP

may represent a novel strategy to potentiate sorafenib responsiveness in HCC.

关键词

Keywords

references

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靶向WTAP通过抑制ERK信号通路增强肝细胞癌对索拉非尼治疗的敏感性

Targeting WTAP sensitizes hepatocellular carcinoma to sorafenib by inhibiting the ERK signaling pathway

DOI：10.1631/jzus.B2500191

摘要

Abstract

关键词

Keywords

references