Fang Min, Li Yongkui, Huang Kai, Qi Shanshan, Zhang Jian, Zgodzinski Witold, Majewski Marek, Wallner Grzegorz, Gozdz Stanislaw, Macek Pawel, Kowalik Artur, Pasiarski Marcin, Grywalska Ewelina, Vatan Linda, Nagarsheth Nisha, Li Wei, Zhao Lili, Kryczek Ilona, Wang Guobin, Wang Zheng, Zou Weiping, Wang Lin
Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Cancer Res. 2017 May 15;77(10):2735-2745. doi: 10.1158/0008-5472.CAN-16-1602. Epub 2017 Mar 1.
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 , respectively. IL33 stimulated cell sphere formation and prevented chemotherapy-induced tumor apoptosis. Mechanistically, IL33 activated core stem cell genes , and / 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, 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. .
白细胞介素33（IL33）在结肠癌中的表达及生物学作用尚不清楚。在本研究中，我们发现IL33在人结肠癌微环境中的血管内皮细胞和肿瘤细胞中表达。给予人IL33和过表达鼠IL33分别增强了人和鼠结肠癌细胞的生长。IL33刺激细胞球形成并防止化疗诱导的肿瘤细胞凋亡。机制上，IL33通过ST2信号通路激活核心干细胞基因，诱导c-Jun氨基末端激酶（JNK）磷酸化激活，并增强c-Jun与核心干细胞基因启动子的结合。此外，IL33将巨噬细胞募集到癌症微环境中，并刺激它们产生前列腺素E，从而支持结肠癌的干性和肿瘤生长。临床上，肿瘤IL33表达与转移性结肠癌患者的不良生存相关。因此，IL33双重靶向肿瘤细胞和巨噬细胞，并赋予结肠癌细胞干细胞样特性以促进肿瘤发生。总之，我们的工作揭示了一种外在赋予癌细胞干细胞特性的免疫相关机制。靶向IL33信号通路可能为治疗转移性癌症患者提供机会。
