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Abstract：
Intermittent hypoxia (IH) is a hallmark of obstructive sleep apnea (OSA), which is related to tumorigenesis and progression. We explored the possible mechanisms by which OSA may promote the development of non-small cell lung cancer (NSCLC). In this study, NSCLC cells with and without miR-106a-5p inhibition were exposed to IH or room air (RA), and subsequently, exosomes were extracted and identified. Macrophages were incubated with these exosomes to detect the expression of the STAT3 signaling pathway and M2-type macrophage markers, as well as the effect of the macrophages on the malignancy of NSCLC cells. A nude mouse tumorigenesis model was constructed to detect the effects of exosomal miR-106a-5p on M2 macrophage polarization and NSCLC cell malignancy. Our results showed that IH exosomes promoted the polarization of M2 macrophages, thereby promoting the proliferation, invasion, and metastasis of NSCLC cells. Further, Based on microarray analysis of RA and IH exosomes, we discovered that miR-106a-5p, transferred to the macrophages through exosomes, participated in this mechanism by promoting M2 macrophage polarization via down-regulating PTEN and activating the STAT3 signaling pathway in vitro and in vivo. For patients with NSCLC and OSA, exosomal miR-106a-5p levels showed a positive relation to AHI. Exosomal miR-106a-5p represents a potential therapeutic target among patients with concomitant cancer and NSCLC.
摘要：
间歇性缺氧（IH）是阻塞性睡眠呼吸暂停（OSA）的标志，这与肿瘤发生和进展有关。我们探讨了OSA可能促进非小细胞肺癌（NSCLC）发展的可能机制。在这项研究中,将具有和不具有miR-106a-5p抑制的NSCLC细胞暴露于IH或室内空气（RA），随后,提取并鉴定外泌体。用这些外泌体孵育巨噬细胞，检测STAT3信号通路和M2型巨噬细胞标志物的表达，以及巨噬细胞对NSCLC细胞恶性程度的影响。构建裸鼠肿瘤发生模型，检测外泌体miR-106a-5p对M2巨噬细胞极化和NSCLC细胞恶性程度的影响。我们的结果表明，IH外泌体促进M2巨噬细胞的极化，从而促进扩散，入侵,和NSCLC细胞的转移。Further,基于RA和IH外泌体的微阵列分析，我们发现miR-106a-5p，通过外泌体转移到巨噬细胞，通过下调PTEN和激活STAT3信号通路促进M2巨噬细胞极化参与了这一机制。对于NSCLC和OSA患者，外泌体miR-106a-5p水平与AHI呈正相关。外泌体miR-106a-5p代表伴随癌症和NSCLC患者中的潜在治疗靶标。
