Vitamin D-mediated tsRNA-07804 triggers mitochondrial dysfunction and suppresses non-small cell lung cancer progression by targeting CRKL.

ABSTRACT

OBJECTIVE: tRNA-derived small RNAs (tsRNAs) are novel non-coding RNAs with various functions in multiple cancers. Nevertheless, whether vitamin D executes its function in mitochondrial dysfunction and non-small cell lung cancer (NSCLC) progression through tsRNAs remains obscure. METHODS: Differentially expressed tsRNAs between control and vitamin D-treated H1299 cells were acquired by small RNA sequencing. Cell and animal experiments were implemented to elucidate the impacts of vitamin D and tsRNA on mitochondrial dysfunction and NSCLC progression. Dual-luciferase reporter assay, quantitative real-time PCR, western blot and recovery experiments were applied to determine the mechanism of tsRNA in NSCLC. RESULTS: We discovered that vitamin D receptor resulted in decreased mitochondrial-related functions and vitamin D caused mitochondrial dysfunction of NSCLC cells. tsRNA-07804 was remarkably upregulated in vitamin D-treated H1299 cells. Functional experiments indicated that vitamin D led to mitochondrial dysfunction, repressed the proliferation, migration, invasion, and promoted apoptosis of H1299 cells via regulating tsRNA-07804. Mechanistically, tsRNA-07804 induced mitochondrial dysfunction and inhibited the malignancy of H1299 cells by suppressing CRKL expression. In vivo experiments showed that vitamin D inhibited the tumor growth in NSCLC by increasing tsRNA-07804 expression. Moreover, clinical sample analysis unveiled that tsRNA-07804 had a negative correlation with CRKL. CONCLUSIONS: In conclusion, our study proved that vitamin D induced mitochondrial dysfunction and suppressed the progression of NSCLC through the tsRNA-07804/CRKL axis. Overall, these results unveiled that tsRNA-07804 might act as a potential therapeutic target for NSCLC.