Ribonuclease 5/Angiogenin Suppresses Intestinal Tumor Initiation by Maintaining Crypt Homeostasis

Ribonuclease 5 (RNase5), also named angiogenin, is generally considered to be pro-tumorigenic. Previous work has shown that RNase5 promotes tumor angiogenesis, accelerates cancer cell proliferation, and enhances migration and invasion. Here, we investigated the role of RNase5 in early tumorigenesis. Contrary to the functions in established disease settings, RNase5 exhibited a dose-dependent suppressive effect on intestinal tumor initiation. Mechanistically, cytoplasmic RNase5 restricted global protein synthesis by producing stress-induced tRNA fragments (tiRNAs) to support intestinal steady state, thus restraining hyperproliferation of crypt stem and transit amplifying cells. Administration of exogenous RNase5 or RNase5-generated tiRNAs during tumorigenesis onset reduced the number and size of adenomas. Furthermore, nested case-control studies revealed that baseline serum RNase5 levels were inversely correlated with colorectal cancer (CRC) development. Together, these findings uncover RNase5 as a key regulation factor that controls intestinal cell malignant transformation and provide intervention options for CRC prevention.