Abstract
BackgroundtRNA-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.MethodstRF3008A (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.ResultsThe 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.ConclusionstRF3008A suppresses the metastasis and progression of colorectal cancer by destabilizing FOXK1 in an AGO-dependent manner.
Highlights
TRNA-derived fragments have been shown to have critical regulatory roles in cancer biology
We detected 1667 distinct Transfer RNAs (tRNAs)-derived fragments (tRFs) in total and 16 differentially expressed tRFs and tiRNAs, among which 9 tRFs from 47 tRNAs were upregulated and 7 tRFs from 38 tRNAs were downregulated in colorectal cancer (CRC) compared with adjacent non-tumorous tissues (ANT) (Table S1)
To further investigate the distinct distribution of tRFs between CRC tissues and adjacent non-tumorous tissues, tRF-5 showed the highest expression in both CRC tissues and ANT, and the expression of tRF-3 was higher in adjacent non-tumorous tissues than those in CRC tissues (Fig. 1D & E)
Summary
TRNA-derived fragments (tRFs) have been shown to have critical regulatory roles in cancer biology. 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. Colorectal cancer (CRC) is one of the most lethal diseases and the third leading cause of cancer-related death [1]. 20 to 30% of human colorectal cancer cases present with metastasis at the time of diagnosis and more than half of CRC patients will develop metastasis mostly to the liver and lung. Signatures including genomic instability and oncogene mutations are already in development for clinical biomarkers in colorectal cancer [3]. The molecular mechanisms under aberrant biological processes are not yet fully understood, continued efforts to investigate novel diagnostic markers and therapeutic targets will lead to the translation of these insights into the clinical arena
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