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

  • Cancer Res. 2026 Jun 1;86(11):2643-2659. doi: 10.1158/0008-5472.CAN-25-1827.
Xiaoliang Shi  #  1  2  3 ,  Jingzhou Chen  #  1  2  3 ,  Rongpan Bai  #  1  2  3 ,  Hao Bai  #  3  4 ,  Yaxin Liu  1 ,  Zhengrong Yao  1 ,  Weiwei Chu  1 ,  Xin Xu  1 ,  Ning Shen  2 ,  Yuanhui Mao  2 ,  Guo-Fu Hu  5 ,  Mingjuan Jin  3  4 ,  Kun Chen  3  4 ,  Jinghao Sheng  1  2  3 ,  Zhengping Xu  1  2  3
Affiliations
  • 1. Department of General Surgery, Institute of Environmental Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2. Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
  • 3. Cancer Center, Zhejiang University, Hangzhou, China.
  • 4. Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 5. Division of Hematology and Oncology, Department of Medicine, Tufts Medical Center, Boston, Massachusetts.
  • # Contributed equally.
PMID: 41734376 DOI: 10.1158/0008-5472.CAN-25-1827
Abstract

Ribonuclease 5 (RNase5), also named angiogenin, is generally considered to be protumorigenic. Previous work has shown that RNase5 promotes tumor angiogenesis, accelerates Cancer cell proliferation, and enhances migration and invasion. In this study, 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 (tiRNA) 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 development. Together, these findings uncover RNase5 as a key regulation factor that controls intestinal cell malignant transformation and provide intervention options for colorectal Cancer prevention.

Significance: RNase5 functions as a tumor suppressor during intestinal tumor initiation, reshaping understanding of the role of RNase5 in Cancer and providing potential approaches for preventing colorectal Cancer development.

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