A Positive Feedback Loop Between Cancer Stem-Like Cells and Tumor-Associated Neutrophils Controls Hepatocellular Carcinoma Progression
A Positive Feedback Loop Between Cancer Stem-Like Cells and Tumor-Associated Neutrophils Controls Hepatocellular Carcinoma Progression
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癌症干细胞样细胞和肿瘤相关中性粒细胞之间的正反馈循环控制肝细胞癌的进展。
DOI：
10.1002/hep.30630
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发表时间：
2019-10-01
期刊：
影响因子：
13.5
通讯作者：
Zhou, Jian
中科院分区：
文献类型：
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作者：
Zhou, Shao-Lai;Yin, Dan;Zhou, Jian
肿瘤相关中性粒细胞（TANs）在肿瘤微环境中的肿瘤发展和进展中起着至关重要的作用。尽管对TAN对肝细胞癌（HCC）进展和预后的贡献的理解有所增加，但TAN与HCC细胞之间的直接相互作用尚未完全了解。在本研究中，我们测试了TANs在体外和体内对肝癌细胞的作用，并探讨了它们之间的相互作用机制。我们的研究结果表明，TANs分泌骨形态发生蛋白2和转化生长因子β 2并触发HCC细胞中microRNA 301 b-3 p（miR-301- 3 p）的表达，随后抑制边缘系统相关膜蛋白（LSAMP）和CYLD赖氨酸63去泛素酶（CYLD）的基因表达，并增加HCC细胞的干细胞特征。这些TAN诱导的HCC干细胞样细胞在核因子κ B信号转导中过度活跃，分泌更高水平的趋化因子（C-X-C基序）配体5（CXCL 5），并招募更多的TAN浸润，表明正反馈回路。在临床HCC样本中，TAN增加与miR-301 b-3 p升高、LSAMP和CYLD表达降低以及核p65积累和CXCL 5表达增加相关，所有这些都可预测患者结局。结论：我们的工作确定了一个控制HCC中癌症干细胞样细胞和TAN的正反馈回路，该回路控制肿瘤进展和患者结局。
Tumor-associated neutrophils (TANs) play a crucial role in tumor development and progression in the cancer microenvironment. Despite increased understanding of TAN contributions to hepatocellular carcinoma (HCC) progression and prognosis, the direct interaction between TANs and HCC cells is not fully understood. In this study, we tested the effect of TANs on HCC cells in vitro and in vivo and investigated the mechanism of interaction between them. Our results showed that TANs secreted bone morphogenetic protein 2 and transforming growth factor beta 2 and triggered microRNA 301b-3p (miR-301-3p) expression in HCC cells, subsequently suppressed gene expression of limbic system-associated membrane protein (LSAMP) and CYLD lysine 63 deubiquitinase (CYLD), and increased stem cell characteristics in HCC cells. These TAN-induced HCC stem-like cells were hyperactive in nuclear factor kappa B signaling, secreted higher levels of chemokine (C-X-C motif) ligand 5 (CXCL5), and recruited more TAN infiltration, suggesting a positive feedback loop. In clinical HCC samples, increased TANs correlated with elevated miR-301b-3p, decreased LSAMP and CYLD expression, and increased nuclear p65 accumulation and CXCL5 expression, all of which predicted patient outcome. Conclusion: Our work identified a positive feedback loop governing cancer stem-like cells and TANs in HCC that controls tumor progression and patient outcome.