PDLIM2 repression by ROS in alveolar macrophages promotes lung tumorigenesis
Liwen Li, Fan Sun, Lei Han, Xujie Liu, Yadong Xiao, Alyssa D. Gregory, Steven D. Shapiro, Gutian Xiao, Zhaoxia Qu
Liwen Li, Fan Sun, Lei Han, Xujie Liu, Yadong Xiao, Alyssa D. Gregory, Steven D. Shapiro, Gutian Xiao, Zhaoxia Qu
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Research Article Oncology

PDLIM2 repression by ROS in alveolar macrophages promotes lung tumorigenesis

Abstract

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.

Authors

Liwen Li, Fan Sun, Lei Han, Xujie Liu, Yadong Xiao, Alyssa D. Gregory, Steven D. Shapiro, Gutian Xiao, Zhaoxia Qu

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Figure 6

PDLIM2 repression in AMs by ROS-activated BACH1.

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PDLIM2 repression in AMs by ROS-activated BACH1. (A) ChIP assays showing...
(A) ChIP assays showing more BACH1 but less Pol II bound to the pdlim2 promoter in RAW264.7 mouse macrophages treated with 500 μM H2O2 for 4 hours (n = 4). (B) Nuclear fraction immunoblotting (IB) showing increased nuclear BACH1 in H2O2-treated RAW264.7 macrophages. (C) qPCR showing decreased Pdlim2 in H2O2-treated RAW264.7 macrophages (normalized to β-actin, n = 5). (D) IB and qPCR assays showing decreased PDLIM2 in RAW264.7 cells transfected with BACH1 (n ≥ 3). (E) qPCR showing decreased Pdlim2 by Lewis lung carcinoma (LLC) cell coculture but recovery by NAC in RAW264.7 cells (n ≥ 3). (F) qPCR showing decreased Pdlim2 in H2O2-treated primary AMs from mice (n = 7). (G) IF analysis showing increased nuclear translocation of BACH1 in the AMs of mice with lung tumors (n = 3). (H) IF analysis showing inhibition of BACH1 nuclear translocation in the AMs of mice with lung tumors by in vivo NAC treatment (n ≥ 3). (I) qPCR showing increased Pdlim2 in the AMs of mice with lung tumors by in vivo NAC treatment (n ≥ 3). (J) IF assays showing PDLIM2 induction in the AMs of mice with lung tumors by in vivo NAC treatment (n ≥ 3). (K) Tumor examination showing NAC prevention of lung tumorigenesis in urethane-treated WT mice (n ≥ 3). Experimental schedule of lung tumor induction and in vivo NAC treatment is also shown. Scale bar: 20 μm (G, H, and J). Student’s t test (2 tailed, unpaired) (A, C, D, and F–K) and ordinary 1-way ANOVA (E) were performed, and data represent mean ± SEM in A and C–K. *P < 0.05; **P < 0.01.