IL33 Promotes Colon Cancer Cell Stemness via JNK Activation and Macrophage Recruitment

被引：177

作者：

Fang, Min ^{[1
,2
]}

Li, Yongkui ^{[1
]}

Huang, Kai ^{[3
]}

Qi, Shanshan ^{[1
]}

Zhang, Jian ^{[1
]}

Zgodzinski, Witold ^{[4
]}

Majewski, Marek ^{[4
]}

Wallner, Grzegorz ^{[4
]}

Gozdz, Stanislaw ^{[5
]}

Macek, Pawel ^{[5
]}

Kowalik, Artur ^{[5
]}

Pasiarski, Marcin ^{[5
]}

Grywalska, Ewelina ^{[6
]}

Vatan, Linda ^{[7
]}

Nagarsheth, Nisha ^{[7
]}

Li, Wei ^{[7
,8
]}

Zhao, Lili ^{[9
]}

Kryczek, Ilona ^{[7
]}

Wang, Guobin ^{[8
]}

Wang, Zheng ^{[1
,8
]}

Zou, Weiping ^{[7
]}

Wang, Lin ^{[1
,2
]}

机构：

[1] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Res Ctr Tissue Engn & Regenerat Med, Wuhan, Hubei, Peoples R China

[2] Huazhong Univ Sci & Technol, Union Hosp, Dept Clin Lab, Tongji Med Coll, Wuhan, Hubei, Peoples R China

[3] Huazhong Univ Sci & Technol, Union Hosp, Dept Cardiol, Tongji Med Coll, Wuhan, Hubei, Peoples R China

[4] Med Univ Lublin, Dept Gen Surg 2, Lublin, Poland

[5] Holycross Canc Ctr, Kielce, Poland

[6] Med Univ Lublin, Dept Clin Immunol & Immunotherapy, Lublin, Poland

[7] Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI 48109 USA

[8] Huazhong Univ Sci & Technol, Union Hosp, Dept Gastrointestinal Surg, Tongji Med Coll, Wuhan, Hubei, Peoples R China

[9] Univ Michigan, Dept Biostat, Sch Med, Ann Arbor, MI 48109 USA

来源：

CANCER RESEARCH | 2017年 / 77卷 / 10期

基金：

中国国家自然科学基金;

关键词：

IL-1-LIKE CYTOKINE IL-33; INNATE LYMPHOID-CELLS; T-CELLS; HEPATOCELLULAR-CARCINOMA; TUMOR-IMMUNITY; CD8(+) T; GROWTH; INTERLEUKIN-33; METASTASIS; EXPRESSION;

D O I：

10.1158/0008-5472.CAN-16-1602

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The expression and biological role of IL33 in colon cancer is poorly understood. In this study, we show that IL33 is expressed by vascular endothelial cells and tumor cells in the human colon cancer microenvironment. Administration of human IL33 and overexpression of murine IL33 enhanced human and murine colon cancer cell growth in vivo, respectively. IL33 stimulated cell sphere formation and prevented chemotherapy-induced tumor apoptosis. Mechanistically, IL33 activated core stem cell genes NANOG, NOTCH3, and OCT3/4 via the ST2 signaling pathway, and induced phosphorylation of c-Jun N terminal kinase (JNK) activation and enhanced binding of c-Jun to the promoters of the core stem cell genes. Moreover, IL33 recruited macrophages into the cancer microenvironment and stimulated them to produce prostaglandin E-2, which supported colon cancer stemness and tumor growth. Clinically, tumor IL33 expression associated with poor survival in patients with metastatic colon cancer. Thus, IL33 dually targets tumor cells and macrophages and endows stem-like qualities to colon cancer cells to promote carcinogenesis. Collectively, our work reveals an immune-associated mechanism that extrinsically confers cancer cell stemness properties. Targeting the IL33 signaling pathway may offer an opportunity to treat patients with metastatic cancer. (C) 2017 AACR.

引用

页码：2735 / 2745

页数：11

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