Cancer-associated fibroblast-induced lncRNA UPK1A-AS1 confers platinum resistance in pancreatic cancer via efficient double-strand break repair

• Published in: Oncogene 2022-04, Vol.41 (16), p.2372-2389
• Main Authors: Zhang, Xiang, Zheng, Shangyou, Hu, Chonghui, Li, Guolin, Lin, Hongcao, Xia, Renpeng, Ye, Yuancheng, He, Rihua, Li, Zhihua, Lin, Qing, Chen, Rufu, Zhou, Quanbo
• Format: Article
• Language: English
• Subjects: 101/58; 13/2; 13/31; 14/19; 14/32; 38/39; 38/79; 38/91; 45/77; 59/5; 631/67/1059/2326; 631/67/327; 64/60; 96/21; Adenocarcinoma; Apoptosis; Cancer; Cancer-Associated Fibroblasts - metabolism; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Cell Biology; Cell Line, Tumor; Cell Proliferation; Chemoresistance; DNA damage; DNA repair; Double-strand break repair; Fibroblasts; Gene Expression Regulation, Neoplastic; Human Genetics; Humans; Interleukin 8; Interleukin-8 - genetics; Interleukin-8 - metabolism; Internal Medicine; Medicine; Medicine & Public Health; NF-κB protein; Non-coding RNA; Non-homologous end joining; Oncology; Oxaliplatin; Oxaliplatin - pharmacology; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Paracrine signalling; Phenotypes; Platinum; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Stroma; Therapeutic targets; Tumor cells; Uroplakin Ia
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-022-02253-6

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.