Implication of human endogenous retrovirus W family envelope in hepatocellular carcinoma promotes MEK/ERK-mediated metastatic invasiveness and doxorubicin resistance
Authors: Qiujin Yan
Yan Zhou
Lijuan Liu
Ping Zhou
Honglian Yu
Fan Zhu
Xiaobei Chen
Youyi Liu
Journal: Cell Death Discovery (2021)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Human endogenous retrovirus; HERVs; Syncytin-1; HCC; vascular invasion

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. 

Retracted: No

PubPeer comments:
 In Figure 3F, the mean + SEM are shown for the tumor volume. It is not possible to get SEM down to zero in in vivo experiments like this. Furthermore, in Figure 5E a micrograph has been duplicated, manipulated and presented as something else. ![file] , 
 #1 Thanks you for reminding us. We have contacted the editor to correct the accidental duplication of Fig. 5E. By the way, the volumes of Xenograft tumor of NIH3T3-pCMV were not zero. Because the number of volume is very low, it looks like zero. , 
 #1 Thanks you for reminding us. We have contacted the editor to correct the accidental duplication of Fig. 5E. By the way, the volumes of Xenograft tumor of NIH3T3-pCMV were not zero. Because the number of volume is very low, it looks like zero(you can find this in our supplement table S5). , 
 If not zero, I still think your data is very surprising. I have never experienced so low variation in a xenograft experiment. , 
 #4 In xenograft tumor assay, NIH3T3-pCMV cells was used as the negative control. In fact, nude mice injected with NIH3T3-empty vector cells served as the negative control. There are almost no tumors formed in this group, and the number of volume is very low. There are many manuscripts showed the similar results, which is consistent with our result. You can see the figures in these manuscripts: (1) Clin Cancer Res. 2014 Jun 15;20(12):3087-93; (2) Oncogene. 2019 Jun;38(26):5211-5226; (3) Nature. 2008 Oct 16;455(7215):971-4; (4) Oncogene. 2017 Jun 15;36(24):3406-3416; (5) Neoplasia. 2009 Dec;11(12):1272-84; (6) J Transl Med. 2009 Jan 20;7:8; (7) etc. ![file] Clin Cancer Res. 2014 Jun 15;20 ![file] Neoplasia. 2009 Dec;11(12):1272-84 ![file] J Transl Med. 2009 Jan 20;7:8 By the way, we have corrected the Fig.5E in the publication by applying for an erratum. https: www.ncbi.nlm.nih.gov pmc articles PMC8975879 ,