Cancer-associated fibroblast-induced lncRNA UPK1A-AS1 confers platinum resistance in pancreatic cancer via efficient double-strand break repair
Xiang Zhang, Shangyou Zheng, Chonghui Hu, Guolin Li, Hongcao Lin, Renpeng Xia, Yuancheng Ye, Rihua He, Zhihua Li, Qing Lin, Rufu Chen, Quanbo Zhou
Abstract
Abstract 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 CAF R , a CAF subset derived from platinum-resistant PDAC patients, assumes an iCAF phenotype and produces more IL8 than CAF S isolated from platinum-sensitive PDAC patients. CAF R -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.