Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Immunity. 2012 May 25;36(5):742-54. doi: 10.1016/j.immuni.2012.03.012. Epub 2012 Apr 12.
In vitro data suggest that a subgroup of NLR proteins, including NLRP12, inhibits the transcription factor NF-κB, although physiologic and disease-relevant evidence is largely missing. Dysregulated NF-κB activity is associated with colonic inflammation and cancer, and we found Nlrp12(-/-) mice were highly susceptible to colitis and colitis-associated colon cancer. Polyps isolated from Nlrp12(-/-) mice showed elevated noncanonical NF-κB activation and increased expression of target genes that were associated with cancer, including Cxcl13 and Cxcl12. NLRP12 negatively regulated ERK and AKT signaling pathways in affected tumor tissues. Both hematopoietic- and nonhematopoietic-derived NLRP12 contributed to inflammation, but the latter dominantly contributed to tumorigenesis. The noncanonical NF-κB pathway was regulated upon degradation of TRAF3 and activation of NIK. NLRP12 interacted with both NIK and TRAF3, and Nlrp12(-/-) cells have constitutively elevated NIK, p100 processing to p52 and reduced TRAF3. Thus, NLRP12 is a checkpoint of noncanonical NF-κB, inflammation, and tumorigenesis.
体外数据表明，包括 NLRP12 在内的一小部分 NLR 蛋白可抑制转录因子 NF-κB，但生理和与疾病相关的证据在很大程度上仍然缺乏。NF-κB 活性失调与结肠炎症和癌症有关，我们发现 Nlrp12(-/-) 小鼠极易发生结肠炎和结肠炎相关结肠癌。从 Nlrp12(-/-) 小鼠分离出的息肉显示出非经典 NF-κB 激活的升高和与癌症相关的靶基因表达增加，包括 Cxcl13 和 Cxcl12。NLRP12 负调控受影响的肿瘤组织中的 ERK 和 AKT 信号通路。造血和非造血来源的 NLRP12 均有助于炎症，但后者主要有助于肿瘤发生。非经典 NF-κB 途径在 TRAF3 的降解和 NIK 的激活下受到调节。NLRP12 与 NIK 和 TRAF3 相互作用，且 Nlrp12(-/-) 细胞中 NIK、p100 向 p52 的加工和 TRAF3 的减少持续升高。因此，NLRP12 是非经典 NF-κB、炎症和肿瘤发生的检查点。
