Ribonuclease 5 suppresses intestinal tumorigenesis

Understanding on the transformation of normal intestinal tissue to tumor remains incompleted. Ribonuclease 5 (RNase5) was traditionally recognized as a tumor promoter, here we found it exhibited a dose-dependent tumor-inhibitory effect in normal intestine. Functionally, RNase5 controlled crypt stem and transit amplifying cell proliferation rates to maintain homeostasis, thus suppressing tumor initiation. Mechanistically, cytoplasmic RNase5 restricted protein synthesis to an appropriate level by producing tRNA-derived stress-induced tRNA fragments (tiRNAs) to accommodate intestinal steady state. RNase5 supplementation reduced adenomas if administered during tumorigenesis onset but enhanced tumor growth if added during progression stage. Furthermore, our nested case-control study revealed that low serum ANG predicted higher CRC risk. Our finding suggests that RNase5 plays dichotomous roles in intestinal tumor initiation and development, and its serum level may serve as a biomarker for CRC risk predication; its supplementation might be an intervention measure for the population with extremely low serum RNase5. Overall design: To investigate the function of Ribonuclease 5 in intestinal crypt homeostasis, we isolated crypts of WT and RNase5 konckout (KO) mice and performed gene expression profiling analysis using data obtained from RNA-seq, Ribo-seq and small RNA-seq.