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7. ER stress transcription factor Xbp1 suppresses intestinal tumourigenesis

L. Niederreiter1, T. Fritz2, T. Adolph1, A.-M. Krismer2, F. Offner3, S. Hosomi4, M. Tomczak4, B. Enrich2, E. Sarcevic3, M. Tschurtschenthaler2, S. Kempster1, T. Iwawaki5, K. Kohno6, H. Tilg2, R. Blumberg4, A. Kaser1, 1University of Cambridge, Div of Gastroenterology & Hepatology, Dept of Medicine, Cambridge, United Kingdom, 2Innsbruck Medical University, Dept of Medicine II, Innsbruck, Austria, 3Academic Teaching Hospital Feldkirch, Dept of Pathology, Feldkirch, Austria, 4Harvard Medical School, Div of Gastroenterology, Hepatology and Endoscopy, Dept of Medicine, Brigham and Women's Hospital, Boston, United States, 5Gunma University, Advanced Scientific Research Leaders Development Unit, Gunma, Japan, 6Nara Institute of Science and Technology, Laboratory of Molecular and Cell Genetics, Nara, Japan

Background

The unfolded protein response (UPR) allows cells to cope with endoplasmic reticulum (ER) stress. Cancer cells exhibit ER stress as a consequence of the tumour microenvironment characterized by low oxygen, nutrient deprivation and pH changes. Deletion of the UPR transcription factor X-box binding protein-1 (XBP1) in the intestinal epithelium results in unabated ER stress and spontaneous intestinal inflammation. Rare functional variants of XBP1 are associated with inflammatory bowel disease (IBD) and IBD patients typically exhibit unresolved ER stress in intestinal epithelial cells (IECs). Long standing IBD increases the risk to develop colitis-associated cancer.

We hypothesised that unresolved ER stress due to XBP1-deficiency might affect intestinal regeneration, which may impact on tumourigenesis.

Methods

NFκB and Stat3 activation was analysed by immunoblot and immunohistochemistry. S3I-201 and BAY11–7082, specific inhibitors of Stat3 and NFκB, respectively, were administered to Xbp1flox/flox VillinCre mice. Epithelial proliferation was assessed by bromodeoxyuridine (BrdU) staining. Xbp1flox/flox VillinCre mice were studied in a colitis-associated cancer model (AOM/DSS).

Results

Unresolved ER stress in XBP1-deficient mice activates Stat3 in transit amplifying (TA) cells. TA cells are numerically increased in Xbp1−/−(IEC) mice, which is associated with an increased proliferative output of IECs. Administration of the Stat3 inhibitor S3I-201 abrogated epithelial regeneration. IECs of XBP1-deficient mice exhibit increased activation of NFκB, and its blockade with the IKK2 inhibitor BAY11–7082 resulted in abrogation of Stat3 activation. NFκB and Stat3 are engaged in colitis-associated cancer and XBP1-deficient mice exhibit a 10-fold increase in tumour burden in a model of colitis-associated cancer.

Conclusion

Our data reveal an unexpected role of the UPR in intestinal tumourigenesis in that XBP1 acts to restrain tumours. This challenges the current paradigm that malignant cells require an unimpaired UPR for survival. NFκB and Stat3 signaling, which are mechanistically linked to colitis-associated tumourigenesis, are critically overactivated in XBP1-deficient IECs. Our data show that unresolved ER stress in the intestinal epithelium increases the propensity to develop intestinal tumours.