Mp15-20 Hypoxia-Induced Linc00941/Imp2 Drives Chemoresistance of Basal/Squamous Bladder Cancer Through M6a-Mediated Stabilization of Ipo4

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I (MP15)1 May 2024MP15-20 HYPOXIA-INDUCED LINC00941/IMP2 DRIVES CHEMORESISTANCE OF BASAL/SQUAMOUS BLADDER CANCER THROUGH M6A-MEDIATED STABILIZATION OF IPO4 Yilin Yan Yilin YanYilin Yan View All Author Informationhttps://doi.org/10.1097/01.JU.0001009500.87761.bf.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cisplatin resistance and tumor relapse are the leading causes of the mortality in muscle-invasive bladder cancer (MIBC). Preceding evidence supported that basal/squamous subtype, N6-methyladenosine (m6A) modifications and hypoxia are associated with a reduced chemotherapy response. However, the exact mechanism and their relationship remain largely unknown. METHODS: Using single-cell RNA-sequencing, transcriptomics, and sample analysis, we examined the relationship between the basal/squamous subtype, m6A modulators, and hypoxia. To evaluate the regulatory role of these indicators, functional experiments were conducted both in vitro and in vivo. To uncover the underlying mechanisms, various techniques including immunofluorescence, fluorescent in situ hybridization, RNA pull-down, co-immunoprecipitation, and RNA immunoprecipitation were employed. RESULTS: Our study identified that Insulin-like growth factor-2 mRNA-binding protein 2 (IMP2) was specifically overexpressed in basal/squamous MIBC tissues and correlated with high chemoresistance and poor prognosis. IMP2 inhibition markedly enhanced the sensitivity of BC cells to cisplatin both in vitro and in vivo. Moreover, we observed that LINC00941, induced by HIF-1α-mediated transcriptional activation, specifically bound with IMP2 protein and protecting it from degradation. Mechanistically, IMP2 enhanced the mRNA stability of Importin 4 (IPO4) in an m6A-dependent way, subsequently augmenting the nuclear translocation of CCAAT/enhancer-binding protein delta (C/EBPδ) to activate PRKDC-mediated DNA damage repair in response to cisplatin. IPO4 was required for IMP2-induced chemoresistance and linked to the clinical stage and prognosis of BC patients. CONCLUSIONS: Our research revealed a novel mechanism involving the hypoxia-induced LINC00941-IMP2-IPO4-C/EBPδ signaling axis in the chemoresistance of basal/squamous BC. These findings shed light on potential therapeutic targets to enhance treatment efficacy in chemoresistant BC. Download PPT Source of Funding: This study was supported by the National Natural Science Foundation of China (No. 82072821, No. 92059112), Shanghai Natural Science Foundation of China (23ZR1446000) © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e238 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Yilin Yan More articles by this author Expand All Advertisement PDF downloadLoading ...