LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis

被引：55

作者：

Poffenberger, M. C. ^{[1
,2
]}

Metcalfe-Roach, A. ^{[1
]}

Aguilar, E. ^{[1
,2
]}

Chen, J. ^{[1
,2
]}

Hsu, B. E. ^{[1
,3
]}

Wong, A. H. ^{[1
,2
]}

Johnson, R. M. ^{[1
,4
]}

Flynn, B. ^{[1
,2
]}

Samborska, B. ^{[1
]}

Ma, E. H. ^{[1
,2
]}

Gravel, S-P ^{[1
,5
]}

Tonelli, L. ^{[1
]}

Devorkin, L. ^{[6
]}

Kim, P. ^{[6
]}

Hall, A. ^{[1
,7
]}

Izreig, S. ^{[1
,2
]}

Loginicheva, E. ^{[8
]}

Beauchemin, N. ^{[1
,9
]}

Siegel, P. M. ^{[1
,3
]}

Artyomov, M. N. ^{[8
,10
]}

Lum, J. J. ^{[6
,11
]}

Zogopoulos, G. ^{[1
,7
]}

Blagih, J. ^{[1
,2
]}

Jones, R. G. ^{[1
,2
,12
]}

机构：

[1] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3A 1A3, Canada

[2] McGill Univ, Dept Physiol, Montreal, PQ H3G 1Y6, Canada

[3] McGill Univ, Dept Med, Montreal, PQ H3G 2M1, Canada

[4] Genentech Inc, 1 DNA Way South, San Francisco, CA 94080 USA

[5] Univ Montreal, Fac Pharm, Montreal, PQ H3C 3J7, Canada

[6] BC Canc Agcy, Trev & Joyce Deeley Res Ctr, Victoria, BC V8R 6V5, Canada

[7] McGill Univ, Hlth Ctr, Res Inst, Montreal, PQ H3H 2R9, Canada

[8] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

[9] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada

[10] Washington Univ, Ctr Human Immunol & Immunotherapy Programs, St Louis, MO 63110 USA

[11] Univ Victoria, Dept Biochem & Microbiol, Victoria, BC V8W 2Y2, Canada

[12] Van Andel Res Inst, Ctr Canc & Cell Biol, Grand Rapids, MI 49503 USA

来源：

SCIENCE | 2018年 / 361卷 / 6400期

基金：

加拿大健康研究院;

关键词：

PEUTZ-JEGHERS-SYNDROME; HEMATOPOIETIC STEM-CELLS; GASTRIC TUMORIGENESIS; INTESTINAL POLYPOSIS; KNOCKOUT MICE; METABOLISM; CANCER; INFLAMMATION; STAT3; IL-6;

D O I：

10.1126/science.aan3975

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：406 / 411

页数：6

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