Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
Genome Institute of Singapore, Singapore, Singapore.
Sci Rep. 2019 Feb 6;9(1):1509. doi: 10.1038/s41598-018-36605-8.
We have previously demonstrated the pro-tumoral role of neutrophils using a kras-induced zebrafish hepatocarcinogenesis model. To further illustrate the molecular basis of the pro-tumoral role, Tumor-associated neutrophils (TANs) were isolated by fluorescence-activated cell sorting (FACS) and transcriptomic analyses were carried out by RNA-Seq. Differentially expressed gene profiles of TANs from larvae, male and female livers indicate great variations during liver tumorigenesis, but the common responsive canonical pathways included an immune pathway (Acute Phase Response Signaling), a liver metabolism-related pathway (LXR/RXR Activation) and Thrombin Signaling. Consistent with the pro-tumoral role of TANs, gene module analysis identified a consistent down-regulation of Cytotoxicity module, which may allow continued proliferation of malignant cells. Gene Set Enrichment Analysis indicated up-regulation of several genes promoting angiogenesis. Consistent with this, we found decreased density of blood vessels accompanied with decreased oncogenic liver sizes in neutrophil-depleted larvae. Collectively, our study has indicated some molecular mechanisms of the pro-tumoral roles of TANs in hepatocarcinogenesis, including weakened immune clearance against tumor cells and enhanced function in angiogenesis.
我们之前已经使用 kras 诱导的斑马鱼肝癌发生模型证明了中性粒细胞的促肿瘤作用。为了进一步阐明促肿瘤作用的分子基础，通过荧光激活细胞分选（FACS）分离肿瘤相关中性粒细胞（TAN），并通过 RNA-Seq 进行转录组分析。来自幼虫、雄性和雌性肝脏的 TAN 的差异表达基因图谱表明在肝肿瘤发生过程中存在很大变化，但共同响应的规范途径包括免疫途径（急性期反应信号转导）、与肝脏代谢相关的途径（LXR/RXR 激活）和凝血酶信号转导。与 TAN 的促肿瘤作用一致，基因模块分析鉴定出细胞毒性模块的一致下调，这可能允许恶性细胞的持续增殖。基因集富集分析表明，促进血管生成的几个基因上调。与此一致的是，我们发现中性粒细胞耗竭幼虫中的血管密度降低伴随着致癌性肝脏大小的降低。总之，我们的研究表明了 TAN 在肝癌发生中的促肿瘤作用的一些分子机制，包括对肿瘤细胞的免疫清除作用减弱和促进血管生成的功能增强。
