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Targeting
WTAP sensitizes hepatocellular carcinoma to sorafenib by inhibiting the ERK signaling pathwayTargeting
WTAP sensitizes hepatocellular carcinoma to sorafenib by inhibiting the ERK signaling pathway- 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 - Journal of Zhejiang University-SCIENCE B Journal of Zhejiang University-SCIENCE B Vol. 27, Issue 3, Pages: 310-320(2026)
- 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：
DOI：10.1631/jzus.B2500191
CLC：- CSTR：
Received：16 April 2025，
Revised：2025-06-25，
Published：18 March 2026
- 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
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