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journal article·2025-11Open access

TWF2 Drives Tumor Progression and Sunitinib Resistance in Renal Cell Carcinoma through Hippo Signaling Suppression

Liangmin Fu, Wuyuan Liao, Youyan Tan, Hansen Lin, Kun Ye, Xinwei Zhou, Mingjie Lin, Kangbo Huang, Minyu Chen, Jietao Wei, Haoqian Feng, Yuhang Chen, Jinwei Chen, Bohong Guan, Shan Li, Zhengkun Zhang, Anze Yu, Zihao Feng, Lizhen Zhang, Guannan Shu, Jun Lu, Wei Chen, Yihui Pan, Jiefeng Yang, Junhang Luo, Li Luo

Advanced Science· Volume 12· Issue 44
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Abstract

Abstract Renal cell carcinoma (RCC) remains a formidable clinical challenge, characterized by a high propensity for metastasis and the frequent emergence of intrinsic or acquired resistance to targeted therapies. However, the molecular mechanisms underlying sunitinib resistance and tumor progression in RCC are not fully understood. This study aims to identify Twinfilin actin‐binding protein ( TWF2 ) as a key mediator of tumor aggressiveness and therapeutic resistance. TWF2 expression is markedly upregulated in RCC cells, particularly in sunitinib‐resistant subtypes, and significantly associated with poor prognosis and therapeutic nonresponsiveness. Functional analyses demonstrate that TWF2 promotes RCC cell invasion, migration, metastasis, and sunitinib resistance by inhibiting the Hippo signaling. Mechanistically, TWF2 interacts with Yes‐associated protein (YAP) via the binding residues: TWF2 M99 and YAP M225. By competitively displacing large tumor suppressor kinase 1, TWF2 prevents YAP ubiquitination and degradation, leading to its stabilization and subsequent nuclear translocation. Mutation of the M99 residue abolishes the tumor‐promoting activity of TWF2 . Furthermore, salvianolic acid E is identified as a small‐molecule inhibitor of the TWF2 –YAP interaction, and synergistically enhances sunitinib efficacy in RCC cell lines and patient‐derived xenograft models. These findings highlight TWF2 as a promising therapeutic target for overcoming drug resistance in RCC.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Hippo pathway signaling and YAP/TAZ

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Urology The First Affiliated Hospital of Sun Yat‐sen University Guangzhou Guangdong 518880 China

Digestive Diseases Center Guangdong Provincial Key Laboratory of Digestive Cancer Research The Seventh Affiliated Hospital Sun Yat‐Sen University Shenzhen 528406 China

Department of Urology The Second Xiangya Hospital of Central South University Changsha Hunan 410011 China

Department of Urology Cancer Hospital Chinese Academy of Medical Sciences Shenzhen Center Shenzhen 518116 China

Department of Urology Sun Yat‐sen University Cancer Center Guangzhou 510060 China

State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou 510060 China

Department of Urology Children's Hospital of Chongqing Medical University Chongqing 400014 China

Department of Urology Guangzhou Women and Children's Medical Center Guangzhou Institute of Pediatrics Guangdong Provincial Clinical Research Center for Child Health Guangzhou Medical University Guangzhou 510623 China

Department of Urology the Third Affiliated Hospital of Soochow University Changzhou 213000 China

Department of Oncology The First Affiliated Hospital of Sun Yat‐sen University Guangzhou Guangdong 510080 China

Funding

National Natural Science Foundation of China · National Science Fund for Distinguished Young Scholars · China Postdoctoral Science Foundation · Basic and Applied Basic Research Foundation of Guangdong Province · Natural Science Foundation of Jiangsu Province · Natural Science Research of Jiangsu Higher Education Institutions of China

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