Koblansky A Alicia, Truax Agnieszka D, Liu Rongrong, Montgomery Stephanie A, Ding Shengli, Wilson Justin E, Brickey W June, Mühlbauer Marcus, McFadden Rita-Marie T, Hu Peizhen, Li Zengshan, Jobin Christian, Lund Pauline Kay, Ting Jenny P-Y
The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA; Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
Cell Rep. 2016 Mar 22;14(11):2562-75. doi: 10.1016/j.celrep.2016.02.064. Epub 2016 Mar 10.
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 Apc(min/+) genetic model of sporadic gastrointestinal cancer. NLRX1 attenuated Apc(min/+) 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(-/-)Apc(min/+) 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.
NOD样受体（NLR）蛋白是调节免疫的细胞内固有免疫传感器/受体。这项研究表明，NLRX1通过控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基因敲除小鼠对CAC高度敏感，关键的癌症促进途径包括核因子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）以及白细胞介素6（IL-6）均有所增加。NLRX1的肿瘤抑制功能主要源于非造血细胞区室。这促使人们对散发性胃肠道癌的Apc（min/+）基因模型中NLRX1的功能进行分析。NLRX1减弱了Apc（min/+）结肠肿瘤的发生、细胞增殖、NF-κB、MAPK、STAT3的激活以及IL-6水平。应用抗白细胞介素6受体（IL6R）抗体疗法可减轻Nlrx1基因敲除Apc（min/+）小鼠的肿瘤负担，提高生存率，并降低STAT3的激活。作为一项重要的临床关联，在多个患者队列中，人类结肠癌样本中NLRX1的表达水平低于健康对照。这些数据表明，抗IL6R作为一种潜在的个性化疗法，可用于治疗NLRX1表达降低的结肠癌。
