ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

作者：Niederreiter Lukas; Fritz Teresa M J; Adolph Timon E; Krismer Anna Maria; Offner Felix A; Tschurtschenthaler Markus; Flak Magdalena B; Hosomi Shuhei; Tomczak Michal F; Kaneider Nicole C; Sarcevic Edina; Kempster Sarah L; Raine Tim; Esser Daniela; Rosenstiel Philip; Kohno Kenji; Iwawaki Takao; Tilg Herbert; Blumberg Richard S; Kaser Arthur^*

来源：Journal of Experimental Medicine, 2013, 210(10): 2041-2056.

DOI：10.1084/jem.20122341

Unresolved endoplasmic reticulum (ER) stress in the epithelium can provoke intestinal inflammation. Hypomorphic variants of ER stress response mediators, such as X-box-binding protein 1 (XBP1), confer genetic risk for inflammatory bowel disease. We report here that hypomorphic Xbp1 function instructs a multilayered regenerative response in the intestinal epithelium. This is characterized by intestinal stem cell (ISC) expansion as shown by an inositol-requiring enzyme 1 alpha (Ire1 alpha)-mediated increase in Lgr5(+) and Olfm4(+) ISCs and a Stat3-dependent increase in the proliferative output of transit-amplifying cells. These consequences of hypomorphic Xbp1 function are associated with an increased propensity to develop colitis-associated and spontaneous adenomatous polyposis coli (APC)-related tumors of the intestinal epithelium, which in the latter case is shown to be dependent on Ire1 alpha. This study reveals an unexpected role for Xbp1 in suppressing tumor formation through restraint of a pathway that involves an Ire1 alpha- and Stat3-mediated regenerative response of the epithelium as a consequence of ER stress. As such, Xbp1 in the intestinal epithelium not only regulates local inflammation but at the same time also determines the propensity of the epithelium to develop tumors.

• 出版日期2013-9-23