Stress responsive miR-31 is a major modulator of mouse intestinal stem cells during regeneration and tumorigenesis
Yuhua Tian,
Xianghui Ma,
Cong Lv,
Xiaole Sheng,
Xiang Li,
Ran Zhao,
Yongli Song,
Thomas Andl,
Maksim V Plikus,
Jinyue Sun,
Fazheng Ren,
Jianwei Shuai,
Christopher J Lengner,
Wei Cui,
Zhengquan Yu
Affiliations
Yuhua Tian
Beijing Advanced Innovation Center for Food Nutrition and Human Health and State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
Xianghui Ma
Beijing Advanced Innovation Center for Food Nutrition and Human Health and State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
Cong Lv
Beijing Advanced Innovation Center for Food Nutrition and Human Health and State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
Xiaole Sheng
Beijing Advanced Innovation Center for Food Nutrition and Human Health and State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
Xiang Li
Beijing Advanced Innovation Center for Food Nutrition and Human Health and State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
Ran Zhao
Beijing Advanced Innovation Center for Food Nutrition and Human Health and State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
Yongli Song
Beijing Advanced Innovation Center for Food Nutrition and Human Health and State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
Thomas Andl
Vanderbilt University Medical Center, Nashville, United States
Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, Center for Complex Biological Systems, University of California, Irvine, Irvine, United States
Jinyue Sun
Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, Jinan, China
Fazheng Ren
Beijing Advanced Innovation Center for Food Nutrition and Human Health and State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
Jianwei Shuai
Department of Physics and State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, China
Christopher J Lengner
Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, United States; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States
Beijing Advanced Innovation Center for Food Nutrition and Human Health and State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
Intestinal regeneration and tumorigenesis are believed to be driven by intestinal stem cells (ISCs). Elucidating mechanisms underlying ISC activation during regeneration and tumorigenesis can help uncover the underlying principles of intestinal homeostasis and disease including colorectal cancer. Here we show that miR-31 drives ISC proliferation, and protects ISCs against apoptosis, both during homeostasis and regeneration in response to ionizing radiation injury. Furthermore, miR-31 has oncogenic properties, promoting intestinal tumorigenesis. Mechanistically, miR-31 acts to balance input from Wnt, BMP, TGFβ signals to coordinate control of intestinal homeostasis, regeneration and tumorigenesis. We further find that miR-31 is regulated by the STAT3 signaling pathway in response to radiation injury. These findings identify miR-31 as a critical modulator of ISC biology, and a potential therapeutic target for a broad range of intestinal regenerative disorders and cancers.
