Human Endogenous Retrovirus K (HML-2) Elements in the Plasma of People with Lymphoma and Breast Cancer

Contreras-Galindo, Rafael; Kaplan, Mark H.; Leissner, Philippe; Verjat, Thibault; Ferlenghi, Ilaria; Bagnoli, Fábio; Giusti, Fabiola; Dosik, Michael; Hayes, Daniel F.; Gitlin, Scott D.; Markovitz, David M.

doi:10.1128/jvi.00646-08

Cited by 186 publications

(221 citation statements)

References 58 publications

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“…For insertion polymorphisms, although most HERV families became integrated into the human genome millions of years ago, a new class of insertionally polymorphic HERV-K family members has recently been described (46,47). HERV-K113 and HER-K115 insertion has been reported to be involved in various types of cancer (48)(49)(50)(51). New insertion polymorphism of HERVs could serve as novel genetic risk factors and thus provide new insight for research into HERV LTR and cancer.…”

Section: Effect Of Possible Mechanisms Of Herv Ltr In Cancermentioning

confidence: 99%

The role of human endogenous retroviral long terminal repeat sequences in human cancer (Review)

Zhao

Zhu

2013

International Journal of Molecular Medicine

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Abstract. Human endogenous retrovirus (HERV) and solitary long terminal repeats (LTRs) constitute 8% of the human genome. Although most HERV genes are partially deleted and not intact, HERV LTRs comprise features including promoters, enhancers, selective splicer sites and polyadenylation sites in order to regulate the expression of neighboring genes. Owing to the genetic instability of LTRs, their wide distributions along human chromosomes are not only non-random, but are also correlated with gene density. Considerable evidence indicates that HERV LTRs regulate the expression of their adjacent viral and cellular genes in placental development and tumorigenesis. However, the regulatory mechanism of HERV LTRs on the expression of its neighboring cancer-associated genes in human cancers remains to be elucidated. Insertional mutagenesis, recombination and polymorphism are three principal factors of LTR that contribute to its genetic instability. Moreover, genetic instability, hypomethylation, transactivation and the antisense transcript of LTRs enhance the activity of LTRs and regulate the expression of their adjacent genes in human cancers. Therefore, in the present review, we examined the mechanism of HERV LTRs in tumorigenesis in combination with the structure and function of LTRs.

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Section: Effect Of Possible Mechanisms Of Herv Ltr In Cancermentioning

confidence: 99%

The role of human endogenous retroviral long terminal repeat sequences in human cancer (Review)

Zhao

Zhu

2013

International Journal of Molecular Medicine

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“…HERV type K of the HML2 subtype is the most recently integrated and most intact retrovirus in the human genome (19). These most recently acquired proviruses of the HERV-K family can express viral proteins and produce viral particles (20,21). In previous studies we reported that expression of HERV-K env protein in malignant BC cells was substantially higher than in normal or nonmalignant breast cells (22)(23)(24), suggesting that HERV-K might be reactivated and implicated in carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Innovative Strategies for Breast Cancer Immunotherapy

Wang-Johanning¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information ABSTRACTAntitumor effects of human endogenous retrovirus type K (HERV-K) specific short hairpin RNAs (shRNAs) were determined in vitro and in vivo. We observed expression of HERV-K in breast cancer (BC) and inhibition of BC cell proliferation and induction of apoptosis in BC cells treated with anti-HERV-K antibodies. Furthermore, significantly slower growth was observed in BC cells transfected with a shRNA targeting the HERV-K env mRNA (shRNAenv) compared with a shRNA targeting a scrambled RNA sequence (shRNAc). Significantly reduced numbers of colonies formed in soft agar when HERV-K env was knocked down in BC cell lines, compared to treatment with shRNAc, and significantly reduced tumor sizes and weights were demonstrated in mice xenografted with MDA-MB-231, MDA-MB-435.eb1, and SKBR3 BC cells stably transfected with shRNAenv, compared to cells stably transfected with a shRNAc. Downregulation of HERV-K with its targeting shRNA caused an increase of BC cells in the S phase and a corresponding decrease of cells in the G1 or G2-M. HERV-K viral RNAs were found to be involved in BC tumorigenesis via effects on not only p53 signaling pathways, but also other major signaling pathways that play critically important roles in tumorigenesis. SUBJECT TERMS

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“…Additionally, external stimuli, such as infections, viral transactivators, chemical exposures, cytokines, hormones, and inflammation, can induce expression of these proviruses (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). We and others have shown that HIV-1 infection is associated with increased HERV-K (HML-2) expression in vitro and in vivo (33,(45)(46)(47)(48)(49)(50)(51)(52)(53). Compared to healthy individuals, HIV-1-infected individuals show high levels of HERV-K (HML-2) RNA, DNA, protein, and viral particles in their plasma (45,47,48,50).…”

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confidence: 99%

Regulation of the Human Endogenous Retrovirus K (HML-2) Transcriptome by the HIV-1 Tat Protein

Gonzalez-Hernandez

Cavalcoli

Sartor

et al. 2014

J Virol

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Approximately 8% of the human genome is made up of endogenous retroviral sequences. As the HIV-1 Tat protein activates the overall expression of the human endogenous retrovirus type K (HERV-K) (HML-2), we used next-generation sequencing to determine which of the 91 currently annotated HERV-K (HML-2) proviruses are regulated by Tat. Transcriptome sequencing of total RNA isolated from Tat-and vehicle-treated peripheral blood lymphocytes from a healthy donor showed that Tat significantly activates expression of 26 unique HERV-K (HML-2) proviruses, silences 12, and does not significantly alter the expression of the remaining proviruses. Quantitative reverse transcription-PCR validation of the sequencing data was performed on Tattreated PBLs of seven donors using provirus-specific primers and corroborated the results with a substantial degree of quantitative similarity. IMPORTANCEThe expression of HERV-K (HML-2) is tightly regulated but becomes markedly increased following infection with HIV-1, in part due to the HIV-1 Tat protein.The findings reported here demonstrate the complexity of the genome-wide regulation of HERV-K (HML-2) expression by Tat. This work also demonstrates that although HERV-K (HML-2) proviruses in the human genome are highly similar in terms of DNA sequence, modulation of the expression of specific proviruses in a given biological situation can be ascertained using next-generation sequencing and bioinformatics analysis.

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Human Endogenous Retrovirus K (HML-2) Elements in the Plasma of People with Lymphoma and Breast Cancer

Cited by 186 publications

References 58 publications

The role of human endogenous retroviral long terminal repeat sequences in human cancer (Review)

The role of human endogenous retroviral long terminal repeat sequences in human cancer (Review)

Innovative Strategies for Breast Cancer Immunotherapy

Regulation of the Human Endogenous Retrovirus K (HML-2) Transcriptome by the HIV-1 Tat Protein

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