LncRNA FTX promotes colorectal cancer radioresistance through disturbing redox balance and inhibiting ferroptosis via miR-625-5p/SCL7A11 axis.

Abstract

Background: Radiotherapy is widely employed in colorectal cancer (CRC) treatment, but the occurrence of radioresistance severely limits the clinical benefit to patients and significantly contributes to treatment failure and recurrent metastasis.

Aim: To explore the role and underlying mechanism of the lncRNA FTX in radiotherapy resistance in CRC.

Methods: LncRNA FTX expression in colorectal parent cells (HT29 and HCT116) and radioresistant cells (HT29R and HCT116R) was determined by real-time quantitative PCR, and the viability of HT29R-shFTX and HCT116R-shFTX cells under ionizing radiation was evaluated using the cell counting kit-8 assay and colony formation experiment. The levels of glutathione and reactive oxygen species in cells after irradiation were determined, and the association between ferroptosis and lncRNA FTX expression in cancer cells was tested. A dual-luciferase assay was used to validate gene interactions. A xenotransplantation mouse model was established to explore the effects of FTX on the CRC tumor radiosensitivity in vivo.

Results: FTX was upregulated in radioresistant CRC cells, and FTX knockdown inhibited cell survival and increased cell ferroptotic death in response to ionizing radiation. Moreover, lncRNA FTX restricted the SLC7A11 expression by sponging with miR-625-5p, and inhibition of the lncRNA FTX or SLC7A11 significantly increased cellular oxidant levels and DNA damage to ionizing radiation in cancer cells. However, SLC7A11 overexpression reversed the effects of decreased FTX levels on ferroptosis and high oxidation levels in cancer cells exposed to ionizing radiation.

Conclusion: Inhibition of the lncRNA FTX/miR-625-5p/SLC7A11 axis can induce ferroptosis and disturb intracellular redox balance, further sensitizing CRC cells to ionizing radiation, suggesting its potential as a therapeutic target for improving CRC response to radiation therapy.