Laboratory of Inflammation and Molecular Pharmacology, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences & Biomedical Research Institute, Hubei University of Medicine, Shiyan 442000, China.
State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Int J Biol Sci. 2021 Feb 17;17(3):869-881. doi: 10.7150/ijbs.56152. eCollection 2021.
Mixed lineage kinase domain-like protein (MLKL) plays an important role in necroptosis, but the role and mechanism of MLKL in intestinal tumorigenesis remain unclear. Here, we found that hematopoietic- and nonhematopoietic-derived MLKL affected intestinal inflammation, but nonhematopoietic-derived MLKL primarily inhibited intestinal tumorigenesis. Loss of MLKL enhanced intestinal regeneration and the susceptibility to intestinal tumorigenesis in mice by hyperactivating the Janus kinase 2 (JAK2)/ signal transducer and activator of transcription 3 (STAT3) axis. Furthermore, MLKL deficiency increased interleukin-6 (IL-6) production in dendritic cells. Administration of anti-IL-6R antibody therapy reduced intestinal tumorigenesis in mice. Notably, low MLKL expression in human colorectal tumors, which enhanced STAT3 activation, was associated with decreased overall survival. Together, our results reveal that MLKL exhibits a suppressive effect during intestinal tumorigenesis by suppressing the IL-6/JAK2/STAT3 signals.
混合谱系激酶结构域样蛋白（MLKL）在坏死性凋亡中发挥重要作用，但 MLKL 在肠道肿瘤发生中的作用和机制尚不清楚。在这里，我们发现造血细胞和非造血细胞衍生的 MLKL 均影响肠道炎症，但非造血细胞衍生的 MLKL 主要抑制肠道肿瘤发生。MLKL 的缺失通过过度激活 Janus 激酶 2（JAK2）/信号转导和转录激活因子 3（STAT3）轴，增强了 小鼠的肠道再生和对肠道肿瘤发生的易感性。此外，MLKL 缺失增加了树突状细胞中白细胞介素 6（IL-6）的产生。抗 IL-6R 抗体治疗降低了 小鼠的肠道肿瘤发生。值得注意的是，人结直肠肿瘤中 MLKL 表达水平较低，激活 STAT3，与总生存率降低相关。总之，我们的结果表明，MLKL 通过抑制 IL-6/JAK2/STAT3 信号通路在肠道肿瘤发生中发挥抑制作用。
