tRF3008A suppresses the progression and metastasis of colorectal cancer by destabilizing FOXK1 in an AGO-dependent manner

Abstract

Background: tRNA-derived fragments (tRFs) have been shown to have critical regulatory roles in cancer biology. However, the contributions of tRFs to colorectal cancer (CRC) remain largely unknown. Methods: tRF3008A (a tRFRNA derived from tRNAVal) was identified by RNA sequencing and validated by quantitative reverse transcription PCR. The role of tRF3008A in CRC progression was assessed both in vitro and in vivo, and its downstream target genes were identified and validated in CRC cells. RNA pull-down with mass spectrometry and AGO-RIP were used to confirm the interaction of tRF3008A and AGO proteins. The clinical implications of tRF3008A were assessed in CRC tissues and blood samples. Results: The expression of tRF3008A was reduced in colorectal cancer, and its reduction was significantly correlated with advanced and metastatic disease in CRC. Patients with low tRF3008A expression showed significantly shorter DFS, and multivariate analysis identified tRF3008A as an independent prognostic biomarker in CRC. Functionally, tRF3008A inhibits the proliferation and migration of CRC in vivo and in vitro by repressing endogenous FOXK1, a positive regulator of the Wnt/β-catenin pathway. Mechanistically, tRF3008A binds to AGO proteins as a guide to destabilize oncogenic FOXK1 transcript. Conclusions: tRF3008A suppresses the metastasis and progression of colorectal cancer by destabilizing FOXK1 in an AGO-dependent manner.