Zhang Lixing, Qiang Jiankun, Yang Xiaoli, Wang Dong, Rehman Adeel Ur, He Xueyan, Chen Weilong, Sheng Dandan, Zhou Lei, Jiang Yi-Zhou, Li Tao, Du Ying, Feng Jing, Hu Xin, Zhang Jian, Hu Xi-Chun, Shao Zhi-Ming, Liu Suling
Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences Shanghai Medical College Key Laboratory of Breast Cancer in Shanghai Innovation Center for Cell Signaling Network Cancer Institute Fudan University Shanghai 200032 China.
Department of Oncology Department of Breast Surgery Shanghai Medical College Fudan University Shanghai 200032 China.
Adv Sci (Weinh). 2019 Nov 13;7(1):1901728. doi: 10.1002/advs.201901728. eCollection 2020 Jan.
Breast tumor initiating cells (BTICs) with ALDHCD24CD44 phenotype are the most tumorigenic and invasive cell population in breast cancer. However, the molecular mechanisms are still unclear. Here, it is found that a negative immune regulator interleukin-1 receptor type 2 (IL1R2) is upregulated in breast cancer (BC) tissues and especially in BTICs. BC patients with high IL1R2 expression have a poorer overall survival and relapse-free survival. High IL1R2 promotes BTIC self-renewal and BC cell proliferation and invasion. Mechanistically, IL1R2 is activated by IL1β, as demonstrated by the fact that IL1β induces the release of IL1R2 intracellular domain (icd-IL1R2) and icd-IL1R2 then interacts with the deubiquitinase USP15 at the UBL2 domain and promotes its activity, which finally induces BMI1 deubiquitination at lysine 81 and stabilizes BMI1 protein. In addition, IL1R2 neutralizing antibody can suppress the protein expression of both IL1R2 and BMI1, and significantly abrogates the promoting effect of IL1R2 on BTIC self-renewal and BC cell growth both in vitro and in vivo. The current results indicate that blocking IL1R2 with neutralizing antibody provides a therapeutic approach to inhibit BC progression by targeting BTICs.
具有ALDHCD24CD44表型的乳腺肿瘤起始细胞（BTICs）是乳腺癌中最具致瘤性和侵袭性的细胞群体。然而，其分子机制仍不清楚。在此研究中，发现负性免疫调节因子白细胞介素1受体2型（IL1R2）在乳腺癌（BC）组织中，尤其是在BTICs中上调。IL1R2高表达的BC患者总生存期和无复发生存期较差。高IL1R2促进BTIC自我更新以及BC细胞增殖和侵袭。机制上，IL1R2被IL1β激活，这表现为IL1β诱导IL1R2胞内结构域（icd-IL1R2）释放，然后icd-IL1R2在UBL2结构域与去泛素化酶USP15相互作用并促进其活性，最终诱导BMI1在赖氨酸81处去泛素化并稳定BMI1蛋白。此外，IL1R2中和抗体可抑制IL1R2和BMI1的蛋白表达，并在体外和体内显著消除IL1R2对BTIC自我更新和BC细胞生长的促进作用。目前的结果表明，用中和抗体阻断IL1R2为通过靶向BTICs抑制BC进展提供了一种治疗方法。
