Integrative multi-omics and single-cell transcriptomics reveal ARHGEF12 driving chemoresistance in bladder cancer

作者：Kunyao Zhu, Zhejiao Zhang, Tinghao Li, Yan Sun, Junlong Zhu, Linfeng Wu, Xiaoyu Zhang, Hang Tong, Zijia Qin, Aimin Wang, Weiyang He · 发表于：Hereditas · 年份：2025 · DOI：10.1186/s41065-025-00606-1 · 被引用次数：2 · 研究领域：Bladder and Urothelial Cancer Treatments、Ferroptosis and cancer prognosis、Genetic Associations and Epidemiology

Bladder cancer (BLCA) is the predominant type of urothelial carcinoma in urinary system, and resistance to cisplatin-based chemotherapy substantially worsens clinical outcomes, presenting a major therapeutic obstacle. In this study, we integrated genome-wide association study (GWAS) data with expression quantitative trait loci (eQTL) analyses, and applied Mendelian randomization (MR) to assess the causal effects of eQTLs from 19,942 genes on BLCA. By incorporating scRNA-seq data, our study also identifies differentially expressed genes (DEGs) in cisplatin-resistant BLCA cells and examined their causal associations with BLCA, aiming to elucidate genetic drivers of chemoresistance and tumor progression. Through this integrated approach, we identified the eQTL of the ARHGEF12 gene as a key mediator of cisplatin resistance. Bioinformatic analysis revealed that elevated ARHGEF12 expression was strongly associated with activation of the PI3K/Akt signaling pathway. To define ARHGEF12's role in cisplatin resistance, we established a cisplatin-resistant UM-UC-3/DDP model. Silencing ARHGEF12 markedly reduced chemoresistance, increased apoptotic cell death, and induced pronounced morphological changes. Pharmacological modulation with the ROCK inhibitor Y-27632 and a rescue assay with the Akt activator SC79 supported a model in which ARHGEF12 drives chemoresistance via RhoA/ROCK-dependent activation of the PI3K/AKT axis. This study is the first to integrate MR with single-cell transcript...