A novel lncRNA FUAT1/TNS4 axis confers chemoresistance by suppressing ROS-mediated apoptosis in gastric cancer

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 lncRNA, designated FUAT1, as a key non-genetic player involved in ROS-mediated intrinsic chemoresistance by employing a unique screening strategy based on transcriptome sequencing (RNA-Seq) technology. To further investigate the 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 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-FU 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 which plays an important 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 overcom chemoresistance.