Abstract：
Aims: Reactive oxygen species (ROS) play a vital role in conveying the cytotoxicity and resistance of most chemotherapy drugs. Therefore, gaining a comprehensive understanding of the intricate activities against oxidative stress in cancer cells may provide valuable insights into the discovery of common mechanisms underlying chemoresistance. Results: We identified a novel long noncoding RNA (lncRNA), designated fluorouracil-associated transcript-1 (FUAT1), as a key nongenetic player involved in ROS-mediated intrinsic chemoresistance by employing a unique screening strategy based on transcriptome sequencing (RNA-Seq) technology. To investigate the precise role of the FUAT1 regulatory axis in chemoresistance, we conducted a series of in vitro and in vivo assays including gain/loss-of-function and rescue experiments. Mechanistically, our findings revealed that FUAT1 upregulates Tensin 4 (TNS4) by sponging miR-140-5p, which allows gastric cancer cells to survive chemotherapy by inhibiting ROS-mediated apoptosis. Clinically, we observed that the FUAT1/TNS4 regulatory axis is negatively associated with overall survival and progression-free survival among gastric and colon cancer patients treated with 5-fluorouracil adjuvant chemotherapy. Innovation: We devised a novel screening strategy distinct from conventional approaches using drug-resistant strains. Through this approach, we identified the previously unrecognized lncRNA FUAT1/TNS4 axis that plays a critical role in ROS-mediated intrinsic chemoresistance. Conclusions: Our findings shed light on fundamental adaptive mechanisms employed by cancer cells to respond to chemotherapy and provide new insights into developing strategies aiming at overcoming chemoresistance.
摘要：
目的：活性氧（ROS）在传递大多数化疗药物的细胞毒性和耐药性中起着至关重要的作用。因此,全面了解癌细胞中复杂的抗氧化应激活性可能为发现化学耐药的共同机制提供有价值的见解。
结果：我们鉴定了一种新的lncRNA，通过采用基于转录组测序（RNA-Seq）技术的独特筛选策略，将FUAT1指定为参与ROS介导的内在化学抗性的关键非遗传参与者。为了进一步研究FUAT1调节轴在化学耐药中的作用，我们进行了一系列的体外和体内试验,包括功能获得/丧失和挽救实验.机械上,我们的发现表明，FUAT1通过海绵作用miR-140-5p上调TNS4，通过抑制ROS介导的细胞凋亡使胃癌细胞在化疗中存活。临床上,我们观察到,在接受5-FU辅助化疗的胃癌和结肠癌患者中,FUAT1/TNS4调节轴与总生存期和无进展生存期呈负相关.
方法：我们设计了一种与使用耐药菌株的常规方法不同的新型筛选策略。通过这种方法，我们鉴定了以前未被识别的lncRNAFUAT1/TNS4轴,该轴在ROS介导的内在化学耐药中起重要作用.
结论：我们的发现揭示了癌细胞对化疗反应的基本适应性机制，并为开发针对过度化疗耐药的策略提供了新的见解。
结果：我们鉴定了一种新的lncRNA，通过采用基于转录组测序（RNA-Seq）技术的独特筛选策略，将FUAT1指定为参与ROS介导的内在化学抗性的关键非遗传参与者。为了进一步研究FUAT1调节轴在化学耐药中的作用，我们进行了一系列的体外和体内试验,包括功能获得/丧失和挽救实验.机械上,我们的发现表明，FUAT1通过海绵作用miR-140-5p上调TNS4，通过抑制ROS介导的细胞凋亡使胃癌细胞在化疗中存活。临床上,我们观察到,在接受5-FU辅助化疗的胃癌和结肠癌患者中,FUAT1/TNS4调节轴与总生存期和无进展生存期呈负相关.
方法：我们设计了一种与使用耐药菌株的常规方法不同的新型筛选策略。通过这种方法，我们鉴定了以前未被识别的lncRNAFUAT1/TNS4轴,该轴在ROS介导的内在化学耐药中起重要作用.
结论：我们的发现揭示了癌细胞对化疗反应的基本适应性机制，并为开发针对过度化疗耐药的策略提供了新的见解。
