Increased autophagy sustains the survival and pro-tumourigenic effects of neutrophils in human hepatocellular carcinoma
Increased autophagy sustains the survival and pro-tumourigenic effects of neutrophils in human hepatocellular carcinoma
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自噬的增加维持中性粒细胞在人肝细胞癌中的存活和促肿瘤作用
DOI：
10.1016/j.jhep.2014.08.023
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发表时间：
2015-01-01
影响因子：
25.7
通讯作者：
Zheng, Limin
中科院分区：
文献类型：
--
作者：
Li, Xue-Feng;Chen, Dong-Ping;Zheng, Limin
背景与目的：中性粒细胞是炎性浸润的常见细胞，在许多癌症中富集。我们最近发现中性粒细胞在人肝细胞癌（HCC）中积累，它们通过释放基质金属蛋白酶-9 （MMP9）促进疾病进展。然而，允许肿瘤微环境教育中性粒细胞的潜在机制在很大程度上是未知的。方法：从HCC患者和健康供体中纯化中性粒细胞。采用免疫组织化学和免疫印迹法评价嗜中性粒细胞自噬作用。通过体外和离体研究评估了嗜中性粒细胞自噬增加的调节和功能。结果：与配对的非肿瘤区域和肿瘤血管内的中性粒细胞相比，HCC肿瘤内区域的大多数中性粒细胞大量表达自噬特异性蛋白LC3。来自肝癌的可溶性因子，包括透明质酸片段，引发中性粒细胞中功能性LC3和自噬体的显著增加，但这与mTOR信号的失活无关。抑制Erk1/2、p38和NF-kappa B信号的激活可以显著减弱这种肿瘤诱导的自噬。这些经历自噬的中性粒细胞表现出长寿的表型，保留了Mcl-1，线粒体明显更完整，以及低裂解的caspase-3，可以通过抑制自噬的开始而被消除。此外，增加的中性粒细胞自噬也与促转移性肿瘤抑制素M和MMP9的持续产生和癌细胞的晚期迁移有关。结论：中性粒细胞自噬的增加可能代表了一种新的机制，将人类的先天反应与肿瘤进展联系起来。研究选择性调节中性粒细胞自噬的机制将为抗癌治疗提供新的策略。(C) 2014欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background & Aims: Neutrophils are common cells of the inflammatory infiltrate and are predominantly enriched in many cancers. We recently found that neutrophils are accumulated in human hepatocellular carcinoma (HCC), where they promote disease progression by releasing matrix metalloproteinase-9 (MMP9). The underlying mechanisms, however, that allow tumour microenvironments to educate neutrophils are largely unknown.Methods: Neutrophils were purified from HCC patients and healthy donors. Immunohistochemistry and immunoblotting were used for the evaluation of autophagy in neutrophils. The regulation and function of increased neutrophil autophagy were assessed by both in vitro and ex vivo studies.Results: Most neutrophils in HCC intratumoural regions, in contrast to those located in the paired non-tumoural areas and within tumour vessels, substantially expressed autophagy-specific protein LC3. Soluble factors derived from hepatoma, including hyaluronan fragments, triggered a considerable increase of functional LC3 and autophagosomes in neutrophils, but this was unrelated to the deactivation of mTOR signalling. Inhibiting the activation of Erk1/2, p38, and NF-kappa B signals could significantly attenuate such tumour-elicited autophagy. These neutrophils, undergoing autophagy, exhibited long-lived phenotypes with retained Mcl-1 and significantly more intact mitochondria as well as low cleaved caspase-3, which could be abolished by inhibiting the initiation of autophagy. Moreover, increased neutrophil autophagy also correlated with sustained production of pro-metastatic oncostatin M and MMP9 and advanced migration of cancer cells.Conclusions: Increased autophagy in neutrophils may represent a novel mechanism that links the innate response to neoplastic progression in humans. Studying the mechanisms that selectively modulate neutrophil autophagy will provide a novel strategy for anti-cancer therapy. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.