JZUS - Journal of Zhejiang University SCIENCE

Journal of Zhejiang University SCIENCE B

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

Author(s): Yu WU, Guomin JU, Xueyu ZHOU, Jian WU, Shusen ZHENG, Chuanhui PENG
Affiliation(s): Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; more
Corresponding email(s): peng_chuanhui@zju.edu.cn, shusenzheng@zju.edu.cn
Key Words: Wilms’ tumor 1-associated protein (WTAP); Sorafenib resistance; Extracellular signal-regulated kinase (ERK) pathway; Hepatocellular carcinoma (HCC)

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Yu WU, Guomin JU, Xueyu ZHOU, Jian WU, Shusen ZHENG, Chuanhui PENG. Targeting WTAP sensitizes hepatocellular carcinoma to sorafenib by inhibiting the ERK signaling pathway[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2500191

@article{title="Targeting WTAP sensitizes hepatocellular carcinoma to sorafenib by inhibiting the ERK signaling pathway",
author="Yu WU, Guomin JU, Xueyu ZHOU, Jian WU, Shusen ZHENG, Chuanhui PENG",
journal="Journal of Zhejiang University Science B",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2500191"
}

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%T Targeting WTAP sensitizes hepatocellular carcinoma to sorafenib by inhibiting the ERK signaling pathway
%A Yu WU
%A Guomin JU
%A Xueyu ZHOU
%A Jian WU
%A Shusen ZHENG
%A Chuanhui PENG
%J Journal of Zhejiang University SCIENCE B
%P 310-320
%@ 1673-1581
%D in press
%I Zhejiang University Press & Springer
doi="https://doi.org/10.1631/jzus.B2500191"

TY - JOUR
T1 - Targeting WTAP sensitizes hepatocellular carcinoma to sorafenib by inhibiting the ERK signaling pathway
A1 - Yu WU
A1 - Guomin JU
A1 - Xueyu ZHOU
A1 - Jian WU
A1 - Shusen ZHENG
A1 - Chuanhui PENG
J0 - Journal of Zhejiang University Science B
SP - 310
EP - 320
%@ 1673-1581
Y1 - in press
PB - Zhejiang University Press & Springer
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doi="https://doi.org/10.1631/jzus.B2500191"

Abstract
Chinese Summary
Academic Network
Reviewer Comment

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. In 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.

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

吴俣^1,2,3,4，琚国民^1,2,3,4，周雪羽⁵，吴健^1,2,3,4，郑树森^1,2,3,4，彭传会^1,2,3,4
¹浙江大学医学院附属第一医院肝胆胰外科，中国杭州，310003
²国家卫健委多器官联合移植重点实验室，浙江省器官移植重点实验室，中国杭州，310003
³器官移植诊断与治疗重点实验室，肝胆胰肿瘤协同诊疗研究单元（中国医学科学院2019RU019），中国杭州，310003
⁴传染病诊治国家重点实验室，国家感染性疾病临床医学研究中心，中国杭州，310003
⁵浙江大学医学院附属第一医院甲状腺外科，中国杭州，310003
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。

关键词组：Wilms瘤1相关蛋白（WTAP）；索拉非尼耐药性；细胞外信号调节激酶（ERK）通路；肝细胞癌（HCC）

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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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