The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals.
The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals.
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DOI：
10.1016/j.celrep.2016.02.064
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发表时间：
2016-03-22
期刊：
影响因子：
8.8
通讯作者：
Ting JP
中科院分区：
文献类型：
--
作者：
Koblansky AA;Truax AD;Liu R;Montgomery SA;Ding S;Wilson JE;Brickey WJ;Mühlbauer M;McFadden RM;Hu P;Li Z;Jobin C;Lund PK;Ting JP
NOD样受体(NLR)蛋白是细胞内调节免疫的先天免疫感受器。这项工作表明，NLRX1通过抑制关键的肿瘤促进途径，在结肠炎相关癌(CAC)和散发性结肠癌中发挥肿瘤抑制作用。NLRX1−/−小鼠对CAC高度易感，表现出核因子κB(NF-κB)、丝裂原活化蛋白激酶(MAPK)、信号转导和转录激活因子3(STAT3)和白介素6(IL-6)等关键促癌途径的增加。NLRX1的抑瘤作用主要来源于非造血室。这促使对NLRX1在散发性胃肠道癌Apcmin/+遗传模型中的功能进行了分析。NLRX1可抑制ApcMin/+结肠癌的发生、细胞增殖、核因子-κB、丝裂原活化蛋白、信号转导通路3的激活和IL-6水平。应用抗白细胞介素6受体(IL6R)抗体治疗可减轻NLRX1Apcmin/+−/−小鼠的肿瘤负担，提高存活率，并减少STAT3的激活。作为一个重要的临床相关性，在多个患者队列中，人类结肠癌样本表达的NLRX1水平低于健康对照。这些数据表明，抗IL6R可能成为NLRX1减少的结肠癌的个性化治疗方法。
NOD-like receptor (NLR) proteins are intracellular innate immune sensors/receptors that regulate immunity. This work shows that NLRX1 serves as a tumor suppressor in colitis-associated cancer (CAC) and sporadic colon cancer by keeping key tumor promoting pathways in check. Nlrx1−/− mice were highly susceptible to CAC, showing increases in key cancer-promoting pathways including nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), and interleukin 6 (IL-6). The tumor-suppressive function of NLRX1 originated primarily from the non-hematopoietic compartment. This prompted an analysis of NLRX1 function in the Apcmin/+ genetic model of sporadic gastrointestinal cancer. NLRX1 attenuated Apcmin/+ colon tumorigenesis, cellular proliferation, NF-κB, MAPK, STAT3 activation, and IL-6 levels. Application of anti-interleukin 6 receptor (IL6R) antibody therapy reduced tumor burden, increased survival, and reduced STAT3 activation in Nlrx1−/−Apcmin/+ mice. As an important clinical correlate, human colon cancer samples expressed lower levels of NLRX1 than healthy controls in multiple patient cohorts. These data implicate anti-IL6R as a potential personalized therapy for colon cancers with reduced NLRX1.