The tumor stroma of pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant and heterogeneous population of cancer-associated fibroblasts (CAFs), which are critically involved in chemoresistance. However, the underlying mechanism of CAFs in chemoresistance is unclear. Here, we show that CAFR, a CAF subset derived from platinum-resistant PDAC patients, assumes an iCAF phenotype and produces more IL8 than CAFS isolated from platinum-sensitive PDAC patients. CAFR-derived IL8 promotes oxaliplatin chemoresistance in PDAC. Based on long noncoding RNA (lncRNA) profiling in tumor cells incubated with CAF-CM, we found that UPK1A-AS1, whose expression is directly induced by IL8/NF-kappa B signaling, functions as a chemoresistance-promoting lncRNA and is critical for active IL8-induced oxaliplatin resistance. Impressively, blocking the activation of UPK1A-AS1 expression increases the oxaliplatin sensitivity of tumor cells in vivo. Mechanistically, UPK1A-AS1 strengthens the interaction between Ku70 and Ku80 to facilitate nonhomologous end joining (NHEJ), thereby enhancing DNA double-strand break (DSB) repair. Clinically, UPK1A-AS1 expression is positively correlated with IL8 expression, a poor chemotherapeutic response and a shorter progression-free survival (PFS) time in advanced PDAC patients. Collectively, our study reveals a lncRNA-mediated mechanism of CAF-derived paracrine IL8-dependent oxaliplatin resistance and highlights UPK1A-AS1 as a potential therapeutic target.

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乐备实（上海优宁维生物科技股份有限公司旗下全资子公司），是国内专注于提供高质量蛋白检测以及组学分析服务的实验服务专家，自2018年成立以来，乐备实不断寻求突破，公司的服务技术平台已扩展到单细胞测序、空间多组学、流式检测、超敏电化学发光、Luminex多因子检测、抗体芯片、PCR Array、ELISA、Elispot、PLA蛋白互作、多色免疫组化、DSP空间多组学等30多个，建立起了一套涵盖基因、蛋白、细胞以及组织水平实验的完整检测体系。

 
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