Drug resistance is the major obstacle of gemcitabine-based chemotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC). Many long non-coding RNAs (lncRNAs) are reported to play vital roles in cancer initiation and progression. Here, we report that lncRNA SLC7A11-AS1 is involved in gemcitabine resistance of PDAC. SLC7A11-AS1 is overexpressed in PDAC tissues and gemcitabine-resistant cell lines. Knockdown of SLC7A11-AS1 weakens the PDAC stemness and potentiates the sensitivity of resistant PDAC cells toward gemcitabine in vitro and in vivo. SLC7A11-AS1 promotes chemoresistance through reducing intracellular reactive oxygen species (ROS) by stabilizing nuclear factor erythroid-2-related factor 2 (NRF2), the key regulator in antioxidant defense. Mechanically, SLC7A11-AS1 is co-localized with β-TRCP1 in the nucleus. The exon 3 of SLC7A11-AS1 interacts with the F-box motif of β-TRCP1, the critical domain that recruits β-TRCP1 to the SCF^β-TRCP E3 complex. This interaction prevents the consequent ubiquitination and proteasomal degradation of NRF2 in the nucleus. Our results demonstrate that the overexpression of SLC7A11-AS1 in gemcitabine-resistant PDAC cells can scavenge ROS by blocking SCF^β-TRCP-mediated ubiquitination and degradation of NRF2, leading to a low level of intracellular ROS, which is required for the maintenance of cancer stemness. These findings suggest SLC7A11-AS1 as a therapeutic target to overcome gemcitabine resistance for PDAC treatment.

耐药是基于吉西他滨的化学疗法治疗胰腺导管腺癌（PDAC）的主要障碍。据报道，许多长的非编码RNA（lncRNA）在癌症的发生和发展中起着至关重要的作用。在这里，我们报告lncRNA SLC7A11-AS1参与PDAC的吉西他滨耐药。SLC7A11-AS1在PDAC组织和吉西他滨耐药细胞系中过表达。敲低的SLC7A11-AS1削弱了PDAC干性并增强耐PDAC细胞向吉西他滨的灵敏度在体外和体内。SLC7A11-AS1通过稳定细胞核中的抗氧化剂防御性关键调节因子erythrroid-2-related factor 2（NRF2）来减少细胞内活性氧（ROS）来增强化学抗性。在机械上，SLC7A11-AS1与β-TRCP1在核中共定位。的外显子3 SLC7A11-AS1相互作用与β-TRCP1，临界域新兵β-TRCP1到SCF的F-box基序^β-TRCP E3复杂。这种相互作用防止了核中NRF2的泛素化和蛋白酶体降解。我们的研究结果表明，吉西他滨耐药的PDAC细胞中SLC7A11-AS1的过表达可以通过阻断SCFβ ^-TRCP清除ROS。介导的NRF2泛素化和降解，导致细胞内ROS含量低，这是维持癌症干性所必需的。这些发现表明，SLC7A11-AS1作为克服吉西他滨对PDAC治疗的耐药性的治疗靶标。