IMP2 drives chemoresistance by repressing cisplatin-induced apoptosis and ferroptosis via activation of IPO4 and SLC7A11 under hypoxia in bladder cancer

作者：Yi‐Lin Yan, Zhengnan Huang, Zhen Zhu, Yang Wang, Xiangqian Cao, Chenkai Yang, Junfeng Jiang, Shujie Xia, Bing Shen · 发表于：Cancer Cell International · 年份：2024 · DOI：10.1186/s12935-024-03570-4 · 被引用次数：13 · 研究领域：RNA modifications and cancer、Ferroptosis and cancer prognosis、Autophagy in Disease and Therapy

BACKGROUND: Cisplatin resistance is the leading cause of mortality in muscle-invasive bladder cancer (MIBC) cases. Previous evidence suggests that abnormal epitranscriptome modifications are associated with reduced chemotherapy responses. However, the exact underlying mechanism remains largely unknown. METHODS: Insulin-like growth factor-2 mRNA-binding protein 2 (IMP2) was identified by clustered regularly interspaced short palindromic repeats (CRISPR) data screening, single-cell RNA-sequencing and sample analysis. To evaluate the regulatory role of IMP2, functional studies were conducted both in vitro and in vivo. To elucidate the underlying mechanisms, various techniques including immunofluorescence, fluorescent in situ hybridization, RNA pull-down, coimmunoprecipitation, and RNA immunoprecipitation were used. RESULTS: Our study revealed that IMP2 was overexpressed in chemoresistant MIBC and lung metastasis tissues. IMP2 inhibition markedly enhanced the sensitivity of BC cells to cisplatin both in vitro and in vivo. Mechanistically, IMP2 enhanced the mRNA stability of IPO4 and SLC7A11 in a m6A-dependent manner, augmenting the nuclear translocation of C/EBPδ to activate PRKDC-mediated DNA damage repair in response to cisplatin. Moreover, IMP2 upregulated SLC7A11 levels and suppressed cisplatin-induced ferroptosis. Combining ferroptosis and apoptosis inhibitors completely reversed cisplatin resistance caused by IMP2 overexpression. LINC00941, which was induced by HIF-1α-media...