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Cancer Res. 2017 May 15;77(10):2735-2745. doi: 10.1158/0008-5472.CAN-16-1602. Epub 2017 Mar 1.

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

Author information

1
Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
2
Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
3
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
4
The Second Department of General Surgery, Medical University in Lublin, Lublin, Poland.
5
Holycross Cancer Center, Kielce, Poland.
6
Department of Clinical Immunology and Immunotherapy, Medical University in Lublin, Lublin, Poland.
7
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
8
Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
9
Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan.
10
Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. lin_wang@hust.edu.cn wzou@med.umich.edu zhengwang@hust.edu.cn wgb@hust.edu.cn.
11
Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. lin_wang@hust.edu.cn wzou@med.umich.edu zhengwang@hust.edu.cn wgb@hust.edu.cn.
12
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan. lin_wang@hust.edu.cn wzou@med.umich.edu zhengwang@hust.edu.cn wgb@hust.edu.cn.

Abstract

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 E2, 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. Cancer Res; 77(10); 2735-45. ©2017 AACR.

PMID:
28249897
PMCID:
PMC5760170
DOI:
10.1158/0008-5472.CAN-16-1602
[Indexed for MEDLINE]
Free PMC Article

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