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, TGFb 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.