Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and multiple evidence has confirmed that C5a production is elevated in NSCLC microenvironment. Although NSCLC cell proliferation induced by C5a has been reported, the involved mechanism has not been elucidated. In this study, we examined the proliferation-related genes (i.e., KLF5, GCN5, and GDF15) and C5a receptor (C5aR) expression in tumor tissues as well as C5a concentration in plasma of NSCLC patients, and then determined the roles of KLF5, GCN5, and GDF15 in C5a-triggered NSCLC cell proliferation and the related mechanism both in vitro and in vivo. Our results found that the expression of KLF5, GCN5, GDF15, C5aR, and C5a was significantly upregulated in NSCLC patients. Mechanistic exploration in vitro revealed that C5a could facilitate A549 cell proliferation through increasing KLF5, GCN5, and GDF15 expression. Besides, KLF5 and GCN5 could form a complex, binding to GDF15 promoter in a KLF5-dependent manner and leading to GDF15 gene transcription. More importantly, GCN5-mediated KLF5 acetylation contributing to GDF15 gene transcription and cell proliferation upon C5a stimulation, the region (-103 to +58 nt) of GDF15 promoter which KLF5 could bind to, and two new KLF5 lysine sites (K335 and K391) acetylated by GCN5 were identified for the first time. Furthermore, our experiment in vivo demonstrated that the growth of xenograft tumors in BALB/c nude mice was greatly suppressed by the silence of KLF5, GCN5, or GDF15. Collectively, these findings disclose that C5a-driven KLF5-GCN5-GDF15 axis had a critical role in NSCLC proliferation and might serve as targets for NSCLC therapy.

中文翻译：

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C5a通过依赖GCN5的KLF5乙酰化介导的GDF15基因激活，诱导非小细胞肺癌的A549细胞增殖。

非小细胞肺癌（NSCLC）是最常见的肺癌类型，多种证据证实，NSCLC微环境中C5a的产生增加。尽管已经报道了由C5a诱导的NSCLC细胞增殖，但是尚未阐明所涉及的机制。在这项研究中，我们检查了NSCLC患者肿瘤组织中与增殖相关的基因（即KLF5，GCN5和GDF15）和C5a受体（C5aR）表达以及C5a浓度，然后确定了KLF5的作用， GCN5和GDF15在C5a触发的NSCLC细胞增殖及相关机制的体内外研究。我们的结果发现，NSCLC患者中KLF5，GCN5，GDF15，C5aR和C5a的表达显着上调。体外机理研究表明，C5a可以通过增加KLF5，GCN5和GDF15的表达来促进A549细胞的增殖。此外，KLF5和GCN5可以形成复合物，以依赖于KLF5的方式与GDF15启动子结合并导致GDF15基因转录。更重要的是，在C5a刺激下，GCN5介导的KLF5乙酰化有助于GDF15基因转录和细胞增殖，KLF5可以结合的GDF15启动子区域（-103至+58 nt）以及两个新的KLF5赖氨酸位点（K335和K391）首次鉴定出由GCN5乙酰化的乙酰化酶。此外，我们的体内实验表明，KLF5，GCN5或GDF15的沉默极大地抑制了BALB / c裸鼠体内异种移植肿瘤的生长。总的来说，