McLoed Allyson G, Sherrill Taylor P, Cheng Dong-Sheng, Han Wei, Saxon Jamie A, Gleaves Linda A, Wu Pingsheng, Polosukhin Vasiliy V, Karin Michael, Yull Fiona E, Stathopoulos Georgios T, Georgoulias Vassilis, Zaynagetdinov Rinat, Blackwell Timothy S
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Cell Rep. 2016 Jun 28;16(1):120-132. doi: 10.1016/j.celrep.2016.05.085. Epub 2016 Jun 16.
Although epithelial NF-κB signaling is important for lung carcinogenesis, NF-κB inhibitors are ineffective for cancer treatment. To explain this paradox, we studied mice with genetic deletion of IKKβ in myeloid cells and found enhanced tumorigenesis in Kras(G12D) and urethane models of lung cancer. Myeloid-specific inhibition of NF-κB augmented pro-IL-1β processing by cathepsin G in neutrophils, leading to increased IL-1β and enhanced epithelial cell proliferation. Combined treatment with bortezomib, a proteasome inhibitor that blocks NF-κB activation, and IL-1 receptor antagonist reduced tumor formation and growth in vivo. In lung cancer patients, plasma IL-1β levels correlated with poor prognosis, and IL-1β increased following bortezomib treatment. Together, our studies elucidate an important role for neutrophils and IL-1β in lung carcinogenesis and resistance to NF-κB inhibitors.
尽管上皮细胞的核因子-κB信号传导对肺癌发生至关重要，但核因子-κB抑制剂对癌症治疗无效。为了解释这一矛盾现象，我们研究了髓系细胞中IKKβ基因缺失的小鼠，发现在Kras(G12D)和肺癌尿烷模型中肿瘤发生增强。髓系特异性抑制核因子-κB可增强中性粒细胞中组织蛋白酶G对白细胞介素-1β前体的加工，导致白细胞介素-1β增加并增强上皮细胞增殖。蛋白酶体抑制剂硼替佐米可阻断核因子-κB激活，联合使用硼替佐米和白细胞介素-1受体拮抗剂可减少体内肿瘤的形成和生长。在肺癌患者中，血浆白细胞介素-1β水平与预后不良相关，硼替佐米治疗后白细胞介素-1β水平升高。总之，我们的研究阐明了中性粒细胞和白细胞介素-1β在肺癌发生和对核因子-κB抑制剂耐药中的重要作用。
