Smoking Increases Transcription of Human Endogenous Retroviruses in a Newly Established <i>in Vitro</i> Cell Model and in Normal Urothelium

Gabriel, Ute; Steidler, Annette; Trojan, Lutz; Michel, Maurice Stephan; Seifarth, Wolfgang; Fabarius, Alice

doi:10.1089/aid.2010.0014

Cited by 19 publications

(17 citation statements)

References 35 publications

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“…As smoking induces several epigenetic changes in urothelial cells (48) it may also affect HERV methylation and contribute to aberrant HERV expression. Additionally, HERVs were reported to become induced by smoking in urothelial cell lines and tissues (49) which may be causative for HERVK17 expression in a few cancer tissues. As the smoking status was not consistently assessed in our patient cohort we cannot confirm these assumptions.…”

Section: Discussionmentioning

confidence: 99%

HERV-K and LINE-1 DNA Methylation and Reexpression in Urothelial Carcinoma

Kreimer¹,

Schulz²,

Koch³

et al. 2013

Front. Oncol.

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Changes in DNA methylation frequently accompany cancer development. One prominent change is an apparently genome-wide decrease in methylcytosine that is often ascribed to DNA hypomethylation at retroelements comprising nearly half the genome. DNA hypomethylation may allow reactivation of retroelements, enabling retrotransposition, and causing gene expression disturbances favoring tumor development. However, neither the extent of hypomethylation nor of retroelement reactivation are precisely known. We therefore assessed DNA methylation and expression of three major classes of retroelements (LINE-1, HERV-K, and AluY) in human urinary bladder cancer tissues and cell lines by pyrosequencing and quantitative reverse transcription–polymerase chain reaction, respectively. We found substantial global LINE-1 DNA hypomethylation in bladder cancer going along with a shift toward full-length LINE-1 expression. Thus, pronounced differences in LINE-1 expression were observed, which may be promoted, among others, by LINE-1 hypomethylation. Significant DNA hypomethylation was found at the HERV-K_22q11.23 proviral long terminal repeat (LTR) in bladder cancer tissues but without reactivation of its expression. DNA methylation of HERVK17, essentially absent from normal urothelial cells, was elevated in cell lines from invasive bladder cancers. Accordingly, the faint expression of HERVK17 in normal urothelial cells disappeared in such cancer cell lines. Of 16 additional HERV-Ks, expression of 7 could be detected in the bladder, albeit generally at low levels. Unlike in prostate cancers, none of these showed significant expression changes in bladder cancer. In contrast, expression of the AluYb8 but not of the AluYa5 family was significantly increased in bladder cancer tissues. Collectively, our findings demonstrate a remarkable specificity of changes in expression and DNA methylation of retroelements in bladder cancer with a significantly different pattern from that in prostate cancer.

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Section: Discussionmentioning

confidence: 99%

HERV-K and LINE-1 DNA Methylation and Reexpression in Urothelial Carcinoma

Kreimer¹,

Schulz²,

Koch³

et al. 2013

Front. Oncol.

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“…69 Urine from smokers has also been shown to lead to an increase in HERV expression in normal human dermal fibroblasts and urothelium in vitro. 70 Other factors that may activate or be activated by HERV-K include infectious viruses such as EBV 71 and human immunodeficiency virus (HIV-1), 72 and transcription factors including NF-jB, NF-AT, 73 MITF-M, 74 Sp1, Sp3 75 and YY1. 76…”

Section: Mechanisms Of Herv Activation and Regulationmentioning

confidence: 99%

Human endogenous retrovirus K and cancer: Innocent bystander or tumorigenic accomplice?

et al. 2014

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Harbored as relics of ancient germline infections, human endogenous retroviruses (HERVs) now constitute up to 8% of our genome. A proportion of this sequence has been co-opted for molecular and cellular processes, beneficial to human physiology, such as the fusogenic activity of the envelope protein, a vital component of placentogenesis. However, the discovery of high levels of HERV-K mRNA and protein and even virions in a wide array of cancers has revealed that HERV-K may be playing a more sinister role–a role as an etiological agent in cancer itself. Whether the presence of this retroviral material is simply an epiphenomenon, or an actual causative factor, is a hotly debated topic. This review will summarize the current state of knowledge regarding HERV-K and cancer and attempt to outline the potential mechanisms by which HERV-K could be involved in the onset and promotion of carcinogenesis.

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“…Environmental factors − both exogenous (chemicals [35], UV radiation, [34,69,70], smoking [71], viruses [72]) and endogenous (estrogen [36], and cytokines [37]) − facilitate HERV expression;…”

Section: Discussionmentioning

confidence: 99%

Human endogenous retroviruses and cancer prevention: evidence and prospects

et al. 2013

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BackgroundCancer is a significant and growing problem worldwide. While this increase may, in part, be attributed to increasing longevity, improved case notifications and risk-enhancing lifestyle (such as smoking, diet and obesity), hygiene-related factors resulting in immuno-regulatory failure may also play a major role and call for a revision of vaccination strategies to protect against a range of cancers in addition to infections.DiscussionHuman endogenous retroviruses (HERVs) are a significant component of a wider family of retroelements that constitutes part of the human genome. They were originated by the integration of exogenous retroviruses into the human genome millions of years ago. HERVs are estimated to comprise about 8% of human DNA and are ubiquitous in somatic and germinal tissues.Physiologic and pathologic processes are influenced by some biologically active HERV families. HERV antigens are only expressed at low levels by the host, but in circumstances of inappropriate control their genes may initiate or maintain pathological processes. Although the precise mechanism leading to abnormal HERVs gene expression has yet to be clearly elucidated, environmental factors seem to be involved by influencing the human immune system.HERV-K expression has been detected in different types of tumors.Among the various human endogenous retroviral families, the K series was the latest acquired by the human species. Probably because of its relatively recent origin, the HERV-K is the most complete and biologically active family.The abnormal expression of HERV-K seemingly triggers pathological processes leading to melanoma onset, but also contributes to the morphological and functional cellular modifications implicated in melanoma maintenance and progression.The HERV-K-MEL antigen is encoded by a pseudo-gene incorporated in the HERV-K env-gene. HERV-K-MEL is significantly expressed in the majority of dysplastic and normal naevi, as well as other tumors like sarcoma, lymphoma, bladder and breast cancer. An amino acid sequence similar to HERV-K-MEL, recognized to cause a significant protective effect against melanoma, is shared by the antigenic determinants expressed by some vaccines such as BCG, vaccinia virus and the yellow fever virus.HERV-K are also reactivated in the majority of human breast cancers. Monoclonal and single-chain antibodies against the HERV-K Env protein recently proved capable of blocking the proliferation of human breast cancer cells in vitro, inhibiting tumor growth in mice bearing xenograft tumors.SummaryA recent epidemiological study provided provisional evidence of how melanoma risk could possibly be reduced if the yellow fever virus vaccine (YFV) were received at least 10 years before, possibly preventing tumor initiation rather than culling melanoma cells already compromised. Further research is recommended to confirm the temporal pattern of this protection and eliminate/attenuate the potential role of relevant confounders as socio-economic status and other vaccinations.It appears also appropr...

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Smoking Increases Transcription of Human Endogenous Retroviruses in a Newly Established in Vitro Cell Model and in Normal Urothelium

Cited by 19 publications

References 35 publications

HERV-K and LINE-1 DNA Methylation and Reexpression in Urothelial Carcinoma

HERV-K and LINE-1 DNA Methylation and Reexpression in Urothelial Carcinoma

Human endogenous retrovirus K and cancer: Innocent bystander or tumorigenic accomplice?

Human endogenous retroviruses and cancer prevention: evidence and prospects

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