Mechanism of NUMBL enhancing axitinib resistance in clear cell renal cell carcinoma by UCHL1-mediated deubiquitination of MMP9
Year: 2025
Type: article
Abstract: from 218.3 μM to 113.2 μM, thereby restoring drug sensitivity. Mechanistically, NUMBL upregulates ubiquitin C-terminal hydrolase L1 (UCHL1). UCHL1 then interacts with and deubiquitinates matrix metalloproteinase 9 (MMP9), leading to MMP9 protein stabilization and increased expression. This cascade ultimately promotes vasculogenic mimicry (VM), a nonangiogenic vascularization process that contributes to axitinib resistance. Our research elucidates this novel NUMBL/UCHL1/MMP9 axis in driving VM-mediated resistance at molecular, cellular, tissue, and animal levels. By integrating the roles of NUMBL, VM, and deubiquitination, this work establishes a theoretical foundation for understanding axitinib resistance and provides new perspectives for improving ccRCC treatment efficacy.
Source: Journal of Biological Chemistry
Authors: Ziyi Wang, Lian Chen, Hang Zhang, Zhiliang Yan, Kailong Liu, Jinchun Qi, Baosai Lu, Yuewei Yin, Chenming Zhao, Yalin Niu, Wei Li
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,430
Awards: G180681395, G866760459
OpenAlex ID: W4415679217