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

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          Abstract

          X-box–binding protein 1 suppresses tumor formation in the gut by regulating Ire1α and Stat3-mediated regenerative responses in the epithelium as a consequence of ER stress.

          Abstract

          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 1α (Ire1α)–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 Ire1α. This study reveals an unexpected role for Xbp1 in suppressing tumor formation through restraint of a pathway that involves an Ire1α- 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.

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          Most cited references52

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          Patterns of somatic mutation in human cancer genomes.

          Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.
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            Molecular genetics of colorectal cancer.

            Over the past three decades, molecular genetic studies have revealed some critical mutations underlying the pathogenesis of the sporadic and inherited forms of colorectal cancer (CRC). A relatively limited number of oncogenes and tumor-suppressor genes-most prominently the APC, KRAS, and p53 genes-are mutated in a sizeable fraction of CRCs, and a larger collection of genes that are mutated in subsets of CRC have begun to be defined. Together with DNA-methylation and chromatin-structure changes, the mutations act to dysregulate conserved signaling networks that exert context-dependent effects on critical cell phenotypes, including the regulation of cellular metabolism, proliferation, differentiation, and survival. Much work remains to be done to fully understand the nature and significance of the individual and collective genetic and epigenetic defects in CRC. Some key concepts for the field have emerged, two of which are emphasized in this review. Specifically, the gene defects in CRC often target proteins and pathways that exert pleiotropic effects on the cancer cell phenotype, and particular genetic and epigenetic alterations are linked to biologically and clinically distinct subsets of CRC.
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                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                23 September 2013
                : 210
                : 10
                : 2041-2056
                Affiliations
                [1 ]Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, England, UK
                [2 ]Department of Internal Medicine II , [3 ]Christian Doppler Research Laboratory for Gut Inflammation , and [4 ]Department of Internal Medicine I, Innsbruck Medical University, A-6020 Innsbruck, Austria
                [5 ]Department of Pathology, Academic Teaching Hospital Feldkirch, A-6800 Feldkirch, Austria
                [6 ]Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
                [7 ]Institut für Klinische Molekularbiologie, Christian-Albrechts-Universität zu Kiel, D-24105 Kiel, Germany
                [8 ]Laboratory of Molecular and Cell Genetics, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan
                [9 ]Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma 371-8511, Japan
                [10 ]Iwawaki Initiative Research Unit, Advanced Science Institute, Institute of Physical and Chemical Research, Wako, Saitama 351-0198, Japan
                Author notes
                CORRESPONDENCE Arthur Kaser: ak729@ 123456cam.ac.uk OR Richard S. Blumberg: rblumberg@ 123456partners.org

                L. Niederreiter and T.M.J. Fritz contributed equally to this paper.

                R.S. Blumberg and A. Kaser contributed equally to this paper.

                A. Kaser began work for this study at the Dept. of Internal Medicine II, Innsbruck Medical University, A-6020 Innsbruck, Austria.

                Article
                20122341
                10.1084/jem.20122341
                3782039
                24043762
                f589a279-1cf6-4383-b031-64c16ea043f2
                © 2013 Niederreiter et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 19 October 2012
                : 7 August 2013
                Categories
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                Medicine
                Medicine

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