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

ABSTRACT: Reactive oxygen species (ROS) play a vital role in conveying the cytotoxicity and resistance of most chemo-drugs. Thus, a better understanding of the detailed activities against oxidative stress in cancer cells may provide novel insights into the discovery of common mechanisms underlying chemoresistance. In this study, taking advantage of a customized screening strategy based on transcriptome sequencing (RNA-Seq) technology, we identified a novel lncRNA, designated FUAT1, as a key non-genetic player that participates in ROS-mediated intrinsic chemoresistance in gastric cancer (GC) cells. The role of the FUAT1 regulatory axis in chemoresistance was further explored by using a series of in vitro and in vivo assays, including gain/loss-of-function and rescue experiments. Mechanistically, FUAT1 could upregulate TNS4 by sponging miR-140-5p, allowing GC cells to survive upon chemotherapy via inhibition of ROS-mediated apoptosis. Clinically, the FUAT1/TNS4 regulatory axis is negatively associated with overall and progression-free survival in gastric and colon cancer patients treated with 5-FU adjuvant chemotherapy. Our findings touch on a fundamental adaptive mechanism for the survival of cancer cells upon chemotherapy, providing a novel insight into the development of strategies to overcome chemoresistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236987 | GEO | 2023/11/30

REPOSITORIES: GEO

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

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

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Project description:Gastric cancer (GC) is a challenging malignant disease among gastrointestinal tumors. The clinical treatments for GC include surgery, neoadjuvant therapy and adjuvant chemotherapy. As patients’ response to chemotherapeutic drugs varies, an approach to predict the efficacy of chemotherapeutic treatment is urgently needed. Here, a biorepository of 17 human gastric tumor organoids (GTOs) and 9 normal organoids (GNOs) derived from GC patients was established, which contains the intestinal, diffuse and mixed-type of GC. GTOs retained morphologic, histopathological and genetic features of the tumors from which they were derived, and patient-derived organoid xenograft model indicated tumorigenicity of organoids. GTOs responses to clinically respective chemotherapy treatment positively correlated with the individual patient’s clinical response. Meanwhile, GNOs, which maintained original characteristics of corresponding tissues, could be separated from GTOs. The use of GNOs predicted the cytotoxic effect of chemotherapy on the organism. Our study implies that patient-derived organoids predict GC patient responses to chemotherapy and provide a solution for personalized treatment.

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