ERBB2 mutations promote recurrence and metastasis in non-muscle-invasive bladder cancer via HIF-1 phosphorylation: Insights from whole exome sequencing

作者：Xu Wang, Long Jin, Xinlin Zou, Ankang Zhu, Mingyu Li, Haitao Fan · 发表于：Journal of Pharmaceutical Analysis · 年份：2025 · DOI：10.1016/j.jpha.2025.101519 · 被引用次数：1 · 研究领域：Bladder and Urothelial Cancer Treatments、Cancer, Hypoxia, and Metabolism、Ferroptosis and cancer prognosis

This study investigates the role of ERBB2 mutations in promoting recurrence and metastasis of non-muscle-invasive bladder cancer (NMIBC). Analysis of whole exome sequencing (WES) data from the The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases revealed a significant association between ERBB2 mutations and immune cell infiltration. To validate these findings, formalin-fixed, paraffin-embedded tumor tissues from patients with recurrent NMIBC were analyzed, with a focus on ERBB2 mutations. In addition, bladder cancer cell lines carrying wild type or mutant ERBB2 were established using clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9) technology. Functional experiments, including Western blotting, protein stability assays, and ubiquitination analyses, demonstrated that ERBB2 mutations promote hypoxia-inducible factor-1 (HIF-1) phosphorylation, leading to its stabilization and enhancing the proliferative, migratory, and invasive capacities of tumor cells. Furthermore, flow cytometry, 5-ethynyl-2'-deoxyuridine (EdU), Cell Counting Kit-8 (CCK-8), and Transwell assays confirmed the impact of these mutations on cellular behavior, while drug sensitivity assays indicated increased susceptibility of ERBB2-mutant cells to therapeutic agents. In vivo studies using mouse models further supported these findings, showing that ERBB2 mutations promote tumor growth, metastasis, and macrophage infiltration...