PDF(Pubmed)
Abstract：
Fusobacterium nucleatum, a gram-negative oral bacterium, has been consistently validated as a strong contributor to the progression of several types of cancer, including colorectal (CRC) and pancreatic cancer. While previous in vitro studies have shown that intracellular F. nucleatum enhances malignant phenotypes such as cell migration, the dependence of this regulation on features of the tumor microenvironment (TME) such as oxygen levels are wholly uncharacterized. Here we examine the influence of hypoxia in facilitating F. nucleatum invasion and its effects on host responses focusing on changes in the global epigenome and transcriptome. Using a multiomic approach, we analyze epigenomic alterations of H3K27ac and global transcriptomic alterations sustained within a hypoxia and normoxia conditioned CRC cell line HCT116 at 24 h following initial infection with F. nucleatum. Our findings reveal that intracellular F. nucleatum activates signaling pathways and biological processes in host cells similar to those induced upon hypoxia conditioning in the absence of infection. Furthermore, we show that a hypoxic TME favors F. nucleatum invasion and persistence and therefore infection under hypoxia may amplify malignant transformation by exacerbating the effects induced by hypoxia alone. These results motivate future studies to investigate host-microbe interactions in tumor tissue relevant conditions that more accurately define parameters for targeted cancer therapies.
摘要：
具核梭杆菌,革兰氏阴性口腔细菌，一直被证明是几种癌症进展的重要因素，包括结直肠癌（CRC）和胰腺癌。虽然以前的体外研究表明，胞内F增强恶性表型，如细胞迁移，这种调节对肿瘤微环境（TME）特征（例如氧水平）的依赖性完全未表征。在这里，我们研究了低氧在促进F.nucleatum入侵中的影响及其对宿主反应的影响，重点是全球表观基因组和转录组的变化。使用多任务方法，我们分析了H3K27ac的表观基因组改变和在缺氧和常氧条件的CRC细胞系HCT116中在最初感染核囊F.我们的发现表明，胞内F.核仁激活宿主细胞中的信号通路和生物学过程，类似于在没有感染的情况下缺氧条件下诱导的信号通路和生物学过程。此外，我们表明，低氧TME有利于F.核仁的侵袭和持续，因此缺氧下的感染可能会加剧缺氧引起的恶性转化。这些结果激发了未来的研究，以调查肿瘤组织相关状况中的宿主-微生物相互作用，从而更准确地定义靶向癌症治疗的参数。
