Implication of human endogenous retrovirus W family envelope in hepatocellular carcinoma promotes MEK/ERK-mediated metastatic invasiveness and doxorubicin resistance.
Implication of human endogenous retrovirus W family envelope in hepatocellular carcinoma promotes MEK/ERK-mediated metastatic invasiveness and doxorubicin resistance.
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人内源性逆转录病毒 W 家族包膜在肝细胞癌中的作用促进 MEK/ERK 介导的转移侵袭性和阿霉素耐药性。
DOI：
10.1038/s41420-021-00562-5
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发表时间：
2021-07-08
影响因子：
7
通讯作者：
Zhu F
中科院分区：
文献类型：
--
作者：
Zhou Y;Liu L;Liu Y;Zhou P;Yan Q;Yu H;Chen X;Zhu F
人类内源性逆转录病毒（Human endogenous retrovirus，HERVs）起源于数百万年前生殖细胞的外源性逆转录病毒感染，具有引起人类疾病的潜能。合胞素-1是由HERV W家族编码的包膜蛋白，参与精神分裂症、多发性硬化症、糖尿病和几种类型的癌症的背景。然而，关于Syncytin-1在HCC中的表达模式及其可能的作用机制尚未见报道。我们发现，与邻近的非肿瘤组织相比，Syncytin-1在HCC中的表达上调，尤其是在晚期HCC中。Syncytin-1是预测HCC患者血管浸润、转移、肿瘤较大和预后不良的独立危险因素。进一步分析发现Syncytin-1过表达与血清HBsAg阳性的HCC患者呈正相关。体外和体内的功能实验表明，Syncytin-1在HCC中增强细胞增殖、转移和致瘤性。京都基因与基因组百科全书（KEGG）通路分析提示，丝裂原活化蛋白激酶（MEK）/细胞外信号调节蛋白激酶（ERK）通路参与了HCC的发生。我们的临床资料表明，磷酸化MEK 1/2和ERK 1/2在HCC中的表达水平高于癌旁组织。HCC中Syncytin-1表达与MEK 1/2和ERK 1/2磷酸化水平上调呈线性相关。此外，Syncytin-1激活肝癌细胞中的MEK/ERK通路。深入的研究表明，炎症激活的MEK/ERK通路在Syncytin-1促进肝癌发生中起着至关重要的作用。Syncytin-1通过MEK/ERK级联抑制阿霉素诱导的细胞凋亡。总之，Syncytin-1通过炎症激活的MEK/ERK途径促进HCC进展和阿霉素耐药。我们的研究结果表明，Syncytin-1是一个潜在的预后生物标志物和治疗肝癌的目标。
Human endogenous retrovirus (HERVs), originating from exogenous retroviral infections of germ cells millions of years ago, have the potential for human diseases. Syncytin-1, an envelope protein encoded by the HERV W family, participates in the contexts of schizophrenia, multiple sclerosis, diabetes, and several types of cancers. Nevertheless, there is no report on the expression pattern and potential mechanism of Syncytin-1 in HCC. Here we found Syncytin-1 expression was up-regulated in HCC compared to adjacent non-tumorous tissues, especially in advanced HCC. Syncytin-1 was an independent risk factor to predict vascular invasion, metastasis, larger tumor size, and poor prognosis in HCC patients. Further analysis discovered that Syncytin-1 overexpression positively associated with HCC patients with serum HBsAg positive. Functional experiments in vitro and in vivo demonstrated that Syncytin-1 enhanced cell proliferation, metastasis, and tumorigenicity in HCC. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that the mitogen-activated protein kinase (MEK)/extracellular signal-regulated protein kinase (ERK) pathway was involved in HCC. Our clinical data indicated that the levels of phosphorylation MEK1/2 and ERK1/2 were increased in HCC comparing with adjacent non-tumorous tissues. It showed the linear correlation between Syncytin-1 expression and upregulated MEK1/2 and ERK1/2 phosphorylation levels in HCC. Furthermore, Syncytin-1 activated MEK/ERK pathway in HCC cells. In-depth research showed that the inflammation-activated MEK/ERK pathway was essential in Syncytin-1 promoted hepatocarcinogenesis. Syncytin-1 suppressed doxorubicin-induced apoptosis via MEK/ERK cascade. In conclusion, Syncytin-1 promoted HCC progression and doxorubicin resistance via the inflammation-activated MEK/ERK pathway. Our findings revealed that Syncytin-1 was a potential prognostic biomarker and therapeutic target for HCC.
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