Abstract

tsRNA-10547 is generated by m 1 A modification-mediated tRNA-Arg-TCT shearing. • tsRNA-10547 suppresses CHRNA9 via binding to AGO2. • tsRNA-10547 promotes the metastasis of colorectal cancer. : Transfer RNA-derived fragments (tsRNAs) were critical regulators in tumorigenesis, yet their specific roles in colorectal cancer (CRC) metastasis remained 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, RIP, and site-directed mutagenesis were performed to explore the molecular mechanism of tsRNA-10547. Here, tsRNA-10547 was significantly upregulated in CRC tumors compared to the 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 m 1 A 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 RISC complex to directly target the 3′UTR of CHRNA9 mRNA, accelerating its degradation and thereby suppressing CHRNA9 expression. In conclusion, TRMT10C-mediated m 1 A modification promotes tsRNA-10547 biogenesis, which degrades CHRNA9 mRNA via 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. Download: Download high-res image (201KB) Download: Download full-size image