| Literature DB >> 30049881 |
M C Poffenberger1,2, A Metcalfe-Roach1, E Aguilar1,2, J Chen1,2, B E Hsu1,3, A H Wong1,2, R M Johnson1,4, B Flynn1,2, B Samborska1, E H Ma1,2, S-P Gravel1,5, L Tonelli1, L Devorkin6, P Kim6, A Hall1,7, S Izreig1,2, E Loginicheva8, N Beauchemin1,9, P M Siegel1,3, M N Artyomov8,10, J J Lum6,11, G Zogopoulos1,7, J Blagih1,2, R G Jones12,2,13.
Abstract
Germline mutations in STK11, which encodes the tumor suppressor liver kinase B1 (LKB1), promote Peutz-Jeghers syndrome (PJS), a cancer predisposition syndrome characterized by the development of gastrointestinal (GI) polyps. Here, we report that heterozygous deletion of Stk11 in T cells (LThet mice) is sufficient to promote GI polyposis. Polyps from LThet mice, Stk11+/- mice, and human PJS patients display hallmarks of chronic inflammation, marked by inflammatory immune-cell infiltration, signal transducer and activator of transcription 3 (STAT3) activation, and increased expression of inflammatory factors associated with cancer progression [interleukin 6 (IL-6), IL-11, and CXCL2]. Targeting either T cells, IL-6, or STAT3 signaling reduced polyp growth in Stk11+/- animals. Our results identify LKB1-mediated inflammation as a tissue-extrinsic regulator of intestinal polyposis in PJS, suggesting possible therapeutic approaches by targeting deregulated inflammation in this disease.Entities:
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Year: 2018 PMID： 30049881 DOI： 10.1126/science.aan3975
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728