Human endogenous retroviral K element encodes fusogenic activity in melanoma cells

Huang, Gengming; Li, Zhongwu; Wan, Xiaohua; Wang, Yue; Dong, Jianli

doi:10.4103/1477-3163.109032

Cited by 37 publications

(20 citation statements)

References 37 publications

(72 reference statements)

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“…So far, a possible relationship of HERVs with chemotherapy resistance might be a result of the interaction of these proteins with cell membrane structure. Hypothetically, the ability of HERV-W E1 and HERV-FRD proteins to promote cell-cell fusion and generation of multinucleated giant cancer cells could represent an alternative membrane-mediated defense mechanism [ 12 , 14 , 15 , 37 , 38 ]. Moreover, HERV overexpression could serve as a benchmark to monitor therapy resistance.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic potential of antiviral drugs targeting chemorefractory colorectal adenocarcinoma cells overexpressing endogenous retroviral elements

Díaz-Carballo¹,

Acikelli²,

Klein³

et al. 2015

J Exp Clin Cancer Res

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BackgroundEndoretroviruses account for circa 8 % of all transposable elements found in the genome of humans and other animals. They represent a genetic footprint of ancestral germ-cell infections of exoviruses that is transmittable to the progeny by Mendelian segregation. Traces of human endogenous retroviruses are physiologically expressed in ovarial, testicular and placental tissues as well as in stem cells. In addition, a number of these fossil viral elements have also been related to carcinogenesis. However, a relation between endoretroviruses expression and chemoresistance has not been reported yet.MethodsTwenty colorectal carcinoma patient samples were scrutinized for HERV-WE1 and HERV-FRD1 endoretroviruses using immunohistochemical approaches. In order to search for differential expression of these elements in chemotherapy refractory cells, a resistant HCT8 colon carcinoma subline was developed by serial etoposide exposure. Endoretroviral elements were detected by immunocytochemical staining, qPCR and ELISA. IC50-values of antiviral and cytostatic drugs in HCT8 cells were determined by MTT proliferation assay. The antivirals-cytostatics interaction was evaluated by the isobologram method.ResultsIn this work, we show for the first time that HERV-WE1, HERV-FRD1, HERV-31, and HERV-V1 are a) simultaneously expressed in treatment-naïve colon carcinoma cells and b) upregulated after cytostatic exposure, suggesting that these retroviral elements are intimately related to chemotherapy resistance. We found a number of antiviral drugs to have cytotoxic activity and the ability to force the downregulation of HERV proteins in vitro. We also demonstrate that the use of different antiviral compounds alone or in combination with anticancer agents results in a synergistic antiproliferative effect and downregulation of different endoretroviral elements in highly chemotherapy-resistant colorectal tumor cells.ConclusionsEnhanced HERV-expression is associated with chemoresistance in colon carcinomas which can be overcome by antiviral drugs alone or in combination with anticancer drugs. Therefore, the introduction of antiviral compounds to the current chemotherapy regimens potentially improves patient outcomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0199-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Therapeutic potential of antiviral drugs targeting chemorefractory colorectal adenocarcinoma cells overexpressing endogenous retroviral elements

Díaz-Carballo¹,

Acikelli²,

Klein³

et al. 2015

J Exp Clin Cancer Res

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“…HERV-K protein expression has been detected in testicular germ cell tumor patients (9) as well as in the plasma samples of lymphoma and breast cancer patients (10). A close association between HERV-K expression and the nonadherent malignant transitions, as well as cell-to-cell fusion of melanoma (11,12), have also been described.…”

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confidence: 86%

HIV-1 Interacts with Human Endogenous Retrovirus K (HML-2) Envelopes Derived from Human Primary Lymphocytes

Brinzevich

Young²,

Sebra

et al. 2014

J Virol

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Human endogenous retroviruses (HERVs) are viruses that have colonized the germ line and spread through vertical passage. Only the more recently acquired HERVs, such as the HERV-K (HML-2) group, maintain coding open reading frames. Expression of HERV-Ks has been linked to different pathological conditions, including HIV infection, but our knowledge on which specific HERV-Ks are expressed in primary lymphocytes currently is very limited. To identify the most expressed HERV-Ks in an unbiased manner, we analyzed their expression patterns in peripheral blood lymphocytes using Pacific Biosciences (PacBio) singlemolecule real-time (SMRT) sequencing. We observe that three HERV-Ks (KII, K102, and K18) constitute over 90% of the total HERV-K expression in primary human lymphocytes of five different donors. We also show experimentally that two of these HERV-K env sequences (K18 and K102) retain their ability to produce full-length and posttranslationally processed envelope proteins in cell culture. We show that HERV-K18 Env can be incorporated into HIV-1 but not simian immunodeficiency virus (SIV) particles. Moreover, HERV-K18 Env incorporation into HIV-1 virions is dependent on HIV-1 matrix. Taken together, we generated high-resolution HERV-K expression profiles specific for activated human lymphocytes. We found that one of the most abundantly expressed HERV-K envelopes not only makes a full-length protein but also specifically interacts with HIV-1. Our findings raise the possibility that these endogenous retroviral Env proteins could directly influence HIV-1 replication. IMPORTANCEHere, we report the HERV-K expression profile of primary lymphocytes from 5 different healthy donors. We used a novel deepsequencing technology (PacBio SMRT) that produces the long reads necessary to discriminate the complexity of HERV-K expression. We find that primary lymphocytes express up to 32 different HERV-K envelopes, and that at least two of the most expressed Env proteins retain their ability to make a protein. Importantly, one of them, the envelope glycoprotein of HERV-K18, is incorporated into HIV-1 in an HIV matrix-specific fashion. The ramifications of such interactions are discussed, as the possibility of HIV-1 target tissue broadening and immune evasion are considered.

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“…Some CrERVs are transcriptionally active in mule deer [12]. Under normal physiological conditions, it is presumed that most ERVs are transcriptionally silenced by the host [9,16] and that failure to do so is associated with disease [17][18][19][20][21]. It is, therefore, extraordinary to have an outbred population in which transcriptionally active ERVs and insertional polymorphism are the norm.…”

Section: Introductionmentioning

confidence: 99%

Computational and Statistical Analyses of Insertional Polymorphic Endogenous Retroviruses in a Non-Model Organism

Bao

Elleder²,

Malhotra³

et al. 2014

Computation

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Human endogenous retroviral K element encodes fusogenic activity in melanoma cells

Cited by 37 publications

References 37 publications

Therapeutic potential of antiviral drugs targeting chemorefractory colorectal adenocarcinoma cells overexpressing endogenous retroviral elements

Therapeutic potential of antiviral drugs targeting chemorefractory colorectal adenocarcinoma cells overexpressing endogenous retroviral elements

HIV-1 Interacts with Human Endogenous Retrovirus K (HML-2) Envelopes Derived from Human Primary Lymphocytes

Computational and Statistical Analyses of Insertional Polymorphic Endogenous Retroviruses in a Non-Model Organism

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