Inactivation of Mind bomb-1 causes the microadenoma coupled with goblet cell hyperplasia

다국어 초록 (Multilingual Abstract)

The Notch pathway plays a central role in many developmental processes by controlling binary cell-fate decisions, and aberrant Notch signaling is of ten associated with tumorigenesis. The activation of Notch signaling promotes tumorigenesis in pre-T cells, but suppresses tumor development in keratinocytes. In the intestine, loss-of-function and gain-of-function studies reveal that Notch signaling regulates cell fate decisions and the inhibition of Notch signaling by a γ-secretase inhibitor turns proliferating cells in adenomas into differentiated goblet cells, suggesting a potential therapeutic benefit in colorectal cancer. Here we show that conditional inactivation of mind bomb-1(mib1), an essential component for generating functional Notch ligands^(10), in the intestinal epithelium causes aberrant crypt formation and goblet cell hyperplasia, coupled with the loss of p21 expression, Wnt overexpression, and β-catenin activation. Interestingly, these mice display microadenomas, similar to the adenomatous foci within human mixed adenomatous-hyperplastic polyps. Our study demonstrates that Mib1 plays a critical role in the early phase of colorectal tumorigenesis and the microadenomatous progression coupled with goblet cell hyperplasia is a novel mechanism that differs from the well-known APC-β-catenin pathway.