肿瘤 NOX4 通过 ROS/PI3K 信号依赖性多种细胞因子产生招募 M2 肿瘤相关巨噬细胞，从而促进 NSCLC 生长。
Tumoral NOX4 recruits M2 tumor-associated macrophages via ROS/PI3K signaling-dependent various cytokine production to promote NSCLC growth.
机构信息
Department of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China; The Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China.
出版信息
Redox Biol. 2019 Apr;22:101116. doi: 10.1016/j.redox.2019.101116. Epub 2019 Feb 6.
M2-type tumor-associated macrophages (TAMs) infiltration contributes to cancer malignant progression. However, the mechanisms for controlling recruitment and M2 polarization of macrophages by cancer cells are largely unclear. NADPH oxidase 4 (NOX4) is abundantly expressed in non-small cell lung cancer (NSCLC) and mediates cancer progression. NOXs are in close relation with cancer-related inflammation, nevertheless, whether tumoral NOXs influence microenvironmental macrophages remains undentified. This study found that there was a close association between NOX4 expression and macrophage chemotaxis in patients with NSCLC analyzed using TCGA RNA-sequencing data. NOX4 in NSCLC cells (A549 and Calu-1 cell lines) efficiently enhanced murine peritoneal macrophage migration and induces M2 polarization. Immunohistochemical analysis of clinical specimens confirmed the positive correlation of NOX4 and CD68 or CD206. The mechanical study revealed that tumoral NOX4-induced reactive oxygen species (ROS) stimulated various cytokine production, including CCL7, IL8, CSF-1 and VEGF-C, via PI3K/Akt signaling-dependent manner. Blockade of the function of these cytokines reversed NOX4 effect on macrophages. Specifically, the results showed that tumoral NOX4-educated M2 macrophages exhibited elevated JNK activity, expressed and released HB-EGF, thus facilitating NSCLC proliferation in vitro. Pretreatment of macrophages with JNK inhibitor blocked tumoral NOX4-induced HB-EGF production in M2 macrophages. Finally, in a xenograft mouse model, overexpression of NOX4 in A549 cells enhanced the tumor growth. Elimination of ROS by NAC or inhibition of NOX4 activity by GKT137831 suppressed tumor growth accompanied by reduction in macrophage infiltration and the percentage of M2 macrophages. In conclusion, our study indicates that tumoral NOX4 recruits M2 TAMs via ROS/PI3K signaling-dependent various cytokine production, thus contributing NSCLC cell growth.
M2 型肿瘤相关巨噬细胞（TAMs）浸润促进癌症恶性进展。然而，癌细胞控制巨噬细胞募集和 M2 极化的机制在很大程度上尚不清楚。NADPH 氧化酶 4（NOX4）在非小细胞肺癌（NSCLC）中大量表达，并介导癌症进展。NOXs 与癌症相关炎症密切相关，然而，肿瘤中的 NOX 是否影响微环境中的巨噬细胞尚不清楚。本研究通过 TCGA RNA 测序数据分析发现，NOX4 表达与 NSCLC 患者的巨噬细胞趋化性密切相关。NSCLC 细胞（A549 和 Calu-1 细胞系）中的 NOX4 有效地增强了小鼠腹腔巨噬细胞的迁移，并诱导了 M2 极化。临床标本的免疫组织化学分析证实了 NOX4 与 CD68 或 CD206 的正相关。机械研究表明，肿瘤中的 NOX4 诱导的活性氧（ROS）通过 PI3K/Akt 信号依赖性方式刺激各种细胞因子的产生，包括 CCL7、IL8、CSF-1 和 VEGF-C。阻断这些细胞因子的功能会逆转 NOX4 对巨噬细胞的作用。具体而言，结果表明，肿瘤中 NOX4 诱导的 M2 巨噬细胞表现出升高的 JNK 活性，表达和释放 HB-EGF，从而促进 NSCLC 在体外的增殖。用 JNK 抑制剂预处理巨噬细胞可阻断 M2 巨噬细胞中 tumoral NOX4 诱导的 HB-EGF 产生。最后，在异种移植小鼠模型中，A549 细胞中 NOX4 的过表达增强了肿瘤的生长。NAC 消除 ROS 或 GKT137831 抑制 NOX4 活性均可抑制肿瘤生长，同时减少巨噬细胞浸润和 M2 巨噬细胞的比例。总之，我们的研究表明，肿瘤中的 NOX4 通过 ROS/PI3K 信号依赖性各种细胞因子的产生招募 M2 TAMs，从而促进 NSCLC 细胞的生长。
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