PDLIM2 repression by ROS in alveolar macrophages promotes lung tumorigenesis
PDLIM2 repression by ROS in alveolar macrophages promotes lung tumorigenesis
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DOI：
10.1172/jci.insight.144394
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发表时间：
2021-03-08
期刊：
影响因子：
8
通讯作者：
Qu, Zhaoxia
中科院分区：
文献类型：
--
作者：
Li, Liwen;Sun, Fan;Qu, Zhaoxia
癌症领域最基本和最具挑战性的问题之一是免疫如何从肿瘤免疫监视转变为促肿瘤炎症。在这里，我们确定了含有肿瘤抑制蛋白 PDZ-LIM 结构域的蛋白 2 (PDLIM2) 作为肺泡巨噬细胞 (AM) 的检查点，对于抑制肺肿瘤非常重要。在肺肿瘤发生过程中，AMs 中的 PDLIM2 表达受到 ROS 激活的转录阻遏蛋白 BTB 和 CNC 同源 1 (BACH1) 的下调。 PDLIM2 下调导致转录因子 STAT3 的组成性激活，驱动 AM 促肿瘤极化/激活以及从循环中吸引的单核细胞分化，从而抑制细胞毒性 T 淋巴细胞并促进肺癌。 PDLIM2 下调也会降低 AM 吞噬作用。这些发现确立了 ROS/BACH1/PDLIM2/STAT3 作为驱动 AM 促进肺肿瘤生长的信号通路。
One of the most fundamental and challenging questions in the field of cancer is how immunity is transformed from tumor immunosurveillance to tumor-promoting inflammation. Here, we identified the tumor suppressor PDZ-LIM domain-containing protein 2 (PDLIM2) as a checkpoint of alveolar macrophages (AMs) important for lung tumor suppression. During lung tumorigenesis, PDLIM2 expression in AMs is downregulated by ROS-activated transcription repressor BTB and CNC homology 1 (BACH1). PDLIM2 downregulation leads to constitutive activation of the transcription factor STAT3, driving AM protumorigenic polarization/activation and differentiation from monocytes attracted from the circulation to suppress cytotoxic T lymphocytes and promote lung cancer. PDLIM2 downregulation also decreases AM phagocytosis. These findings establish ROS/BACH1/PDLIM2/STAT3 as a signaling pathway driving AMs for lung tumor promotion.