tsRNA-10547 generated by m1A modification-mediated tRNA shearing promotes colorectal cancer metastasis via suppressing CHRNA9

Transfer RNA-derived fragments (tsRNAs) are critical regulators in tumorigenesis, yet their specific roles in colorectal Cancer (CRC) metastasis remain poorly characterized. In vitro and in vivo functional experiments were conducted to explore the effects of tsRNA-10547 on the growth and metastasis of CRC. Transcriptome Sequencing, RNA pull-down, RNA immunoprecipitation, and site-directed mutagenesis were performed to explore the molecular mechanism of tsRNA-10547.We found tsRNA-10547 was significantly upregulated in CRC tumors compared to control both in GSE140327 dataset and clinical samples. Overexpression of tsRNA-10547 significantly enhanced CRC cell proliferation, migration, and invasion in vitro, and promoted lung metastasis in vivo. The m¹A methyltransferase TRMT10C, which modified tRNA-Arg-TCT to produce tsRNA-10547, was upregulated in CRC. Orthotopic xenograft experiments demonstrated that TRMT10C promotes CRC lung metastasis through tsRNA-10547. RNA Sequencing identified CHRNA9 as a target gene of tsRNA-10547 and rescue experiments confirmed that tsRNA-10547 facilitates CRC growth and metastasis via inhibition of CHRNA9. Mechanistically, tsRNA-10547 related to Argonaute 2 (AGO2) within the RNA-induced silencing complex to directly target the 3'UTR of CHRNA9 mRNA, accelerating its degradation and thereby suppressing CHRNA9 expression. In conclusion, TRMT10C-mediated m¹A modification promotes tsRNA-10547 biogenesis. tsRNA-10547 then degrades CHRNA9 mRNA by binding to AGO2, accelerating CRC growth and lung metastasis. This study provides crucial insights for preventing CRC metastasis and highlights the translational potential of tsRNAs.