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Abstract：
Interleukin-6 (IL-6)-class inflammatory cytokines signal through the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) pathway and promote the development of pancreatic ductal adenocarcinoma (PDAC); however, the functions of specific intracellular signaling mediators in this process are less well defined. Using a ligand-controlled and pancreas-specific knockout in adult mice, we demonstrate in this study that JAK1 deficiency prevents the formation of KRASG12D-induced pancreatic tumors, and we establish that JAK1 is essential for the constitutive activation of STAT3, whose activation is a prominent characteristic of PDAC. We identify CCAAT/enhancer binding protein δ (C/EBPδ) as a biologically relevant downstream target of JAK1 signaling, which is upregulated in human PDAC. Reinstating the expression of C/EBPδ was sufficient to restore the growth of JAK1-deficient cancer cells as tumorspheres and in xenografted mice. Collectively, the findings of this study suggest that JAK1 executes important functions of inflammatory cytokines through C/EBPδ and may serve as a molecular target for PDAC prevention and treatment.
摘要：
白细胞介素-6(IL-6)类炎性细胞因子通过Janus酪氨酸激酶(JAK)/信号转导和转录激活因子(STAT)通路而促进胰腺导管腺癌(PDAC)的发生发展;在这个过程中，特定的细胞内信号介质的功能不太明确。在成年小鼠中使用配体控制和胰腺特异性敲除，我们在这项研究中证明，JAK1缺乏阻止KRASG12D诱导的胰腺肿瘤的形成，我们确定JAK1对于STAT3的组成型激活至关重要，STAT3的激活是PDAC的突出特征。我们将CCAAT/增强子结合蛋白δ（C/EBPδ）确定为JAK1信号的生物学相关下游靶标，在人类PDAC中上调。恢复C/EBPδ的表达足以恢复缺乏JAK1的癌细胞作为肿瘤球和异种移植小鼠的生长。总的来说，这项研究的结果表明，JAK1通过C/EBPδ执行炎症细胞因子的重要功能，并可能作为PDAC预防和治疗的分子靶标。
