Abstract
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.
Highlights
Human endogenous retrovirus (HERVs), which originate from exogenous retroviral infections of germ cells millions of years ago, are transmitted to the generation in a Mendelian manner along with the human genome [1]
In silico results inhibited Syncytin-1-mediated cell migration by wound healing indicated that mitogen-activated protein kinase (MEK)/extracellular signal-regulated protein kinase (ERK) pathway was implicated in the poor assay (p < 0.01, Fig. 5d) and transwell migration assay
P-ERK1/2 (p < 0.001) levels were found in hepatocellular carcinoma (HCC) specimens. These results suggested that MEK/ERK pathway might be Syncytin-1 prevents doxorubicin-induced apoptosis via MEK/
Summary
Human endogenous retrovirus (HERVs), which originate from exogenous retroviral infections of germ cells millions of years ago, are transmitted to the generation in a Mendelian manner along with the human genome [1]. 1234567890();,: and its capacity to induce inflammation, it will be interesting to showed that the level of Syncytin-1 in HCC was positively investigate the expression pattern of Syncytin-1 in HCC, as well as correlated with vascular invasion (p = 0.004, Fig. 2b, Table 1). In-depth analysis of clinical data results showed that overexpression of Syncytin-1 occurred more indicated that the levels of phosphorylation MEK1/2 and ERK1/ commonly in patients with higher serum AFP levels Survival analysis of our clinical samples showed that overfurther study discovered that Syncytin-1 promoted hepatocarci- expression of Syncytin-1 was positively correlated with poor nogenesis and drug resistance via MEK/ERK pathway. Survival than HCC without the Syncytin-1 overexpression, regardless of the absence or presence of high serum α-fetoprotein (AFP, Fig. 2h, i).
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