Inactivation of the von Hippel-Lindau tumor suppressor leads to selective expression of a human endogenous retrovirus in kidney cancer

Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Oncogene (Impact Factor: 8.46). 05/2011; 30(47):4697-706. DOI: 10.1038/onc.2011.179
Source: PubMed


A human endogenous retrovirus type E (HERV-E) was recently found to be selectively expressed in most renal cell carcinomas (RCCs). Importantly, antigens derived from this provirus are immunogenic, stimulating cytotoxic T cells that kill RCC cells in vitro and in vivo. Here, we show HERV-E expression is restricted to the clear cell subtype of RCC (ccRCC) characterized by an inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene with subsequent stabilization of hypoxia-inducible transcription factors (HIFs)-1α and -2α. HERV-E expression in ccRCC linearly correlated with HIF-2α levels and could be silenced in tumor cells by either transfection of normal VHL or small interfering RNA inhibition of HIF-2α. Using chromatin immunoprecipitation, we demonstrated that HIF-2α can serve as transcriptional factor for HERV-E by binding with HIF response element (HRE) localized in the proviral 5' long terminal repeat (LTR). Remarkably, the LTR was found to be hypomethylated only in HERV-E-expressing ccRCC while other tumors and normal tissues possessed a hypermethylated LTR preventing proviral expression. Taken altogether, these findings provide the first evidence that inactivation of a tumor suppressor gene can result in aberrant proviral expression in a human tumor and give insights needed for translational research aimed at boosting human immunity against antigenic components of this HERV-E.

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    • "and JQ733905). Remarkably, all transcripts derived from the CT-RCC HERV-E were found to be selectively expressed in the clear cell variant of renal cell carcinoma (ccRCC), with no expression observed in normal tissues or any other type of tumor cells (12, 15). Importantly, since proviral expression has been detected in fresh tumors even at the earliest stages of disease, antigens derived from CT-RCC HERV-E could theoretically serve as ideal targets for T-cell based immunotherapy for kidney cancer. "
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    ABSTRACT: Human endogenous retroviruses (HERVs), remnants of ancient germ-line infections with exogenous retroviruses, are estimated to comprise up to 8% of human genome. Most HERVs have accumulated mutations and deletions that prevent their expression as an infectious virus. Nevertheless, a growing number of HERV genes and proteins have been found to be expressed in different cancers, raising the possibility that HERV-derived antigens might represent excellent targets for tumor immunotherapy. Here, we review data showing HERV-encoded antigens are capable of eliciting humoral and T-cells specific antitumor immunity. We also describe a novel HERV-E that was recently found to be selectively expressed in over 80% of clear cell kidney cancer but not in normal tissues. Remarkably, the restricted expression of HERV-E in kidney tumors was found to occur as a consequence of inactivation of the von Hippel-Lindau tumor suppressor. Importantly, antigens derived from this provirus are immunogenic, stimulating cytotoxic T-cells that kill kidney cancer cells in vitro and in vivo. Taken altogether, these data suggest efforts aimed at boosting human immunity against HERV-derived antigens could be used as a strategy to treat advanced tumors including kidney cancer.
    Frontiers in Oncology 09/2013; 3:243. DOI:10.3389/fonc.2013.00243
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    • "Heterochromatin protein 1 (HP-1), a nonhistone chromosomal protein first discovered in Drosophila, can bind to histone methyltransferase and induce aberrant chromatin packaging and gene silencing [2] [3]. Silencing of tumor suppressor genes via methylation of DNA and/or histone has been found to contribute to cancer formation [4] including renal carcinogenesis [5] [6]. The expression of HP-1 has been explored in various tumors including carcinoma of breast [7], colon [8] and prostate [9]. "
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    ABSTRACT: Kidney tumors of various types may behave differently and have different prognosis. Due to some overlapping morphological features and immunohistochemical staining pattern, they may pose diagnostic challenge. Therefore, it is necessary to explore additional immunohistochemical stains to help in subclassifying these epithelial neoplasms. Tissue microarrays of 20 cases each of renal cell carcinomas (RCC) of clear cell, chromophobe, and papillary variants and oncocytoma were constructed and used to test the heterochromatin-associated protein (HP) 1α/β expression. HP-1α/β showed strong nuclear staining. Expression of HP-1α/β was found mostly in papillary RCC (79%) and oncocytoma (75%) but less in chromophobe (30%) and clear cell RCCs (35%). HP-1α/β may be useful in the differential diagnosis of renal tumors, especially in the differentiation of chromophobe RCC and oncocytoma.
    Annals of diagnostic pathology 11/2012; 17(2). DOI:10.1016/j.anndiagpath.2012.10.002 · 1.12 Impact Factor
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    ABSTRACT: Human endogenous retroviruses (HERV) and related elements account for more than 8% of the human genome and significantly contribute to the human transcriptome by long terminal repeat (LTR) promoter activity. In this context, HERVs are thought to intervene in the expression of adjacent genes by providing regulatory sequences (cis-effect) or via noncoding RNA including natural antisense transcripts. To address the potential impact of HERV activity in urothelial carcinoma, we comparatively analyzed the HERV transcription profiles in paired samples of non-malignant urothelium and urothelial carcinoma derived from 13 patients with bladder cancer by means of a retrovirus-specific microarray (RetroArray). We established a characteristic HERV signature consisting of six ubiquitously active HERV subgroups (E4-1, HERV-Rb, ERV9, HERV-K-T47D, NMWV3, HERV-KC4). The transcription pattern is largely identical in human urothelial carcinoma, non-malignant urothelial tissue, four tumor-derived cell lines and in a non-malignant urothelial cell line (UROtsa). Quantitative reverse transcriptase PCR (qRT-PCR) of HERV-E4-1, HERV-K(HML-6) and HERV-T(S71-TK1) revealed a bias to lower HERV activity in carcinoma samples compared to non-malignant tissue. Determination of active HERV-E4-1 loci by cloning and sequencing revealed six HERV-E4-1 proviral loci that are differentially regulated in urothelial carcinoma cells and normal tissue. Two full-length HERV-E4-1 proviruses, HERV-Ec1 and HERV-Ec6, are located in antisense orientation in introns of the genes PLA2G4A and RNGTT, respectively. PLA2G4A encodes a cytosolic phospholipase A2 (cPLA2) that is dysregulated in many human tumors. PLA2G4A and HERV-Ec1 displayed reciprocal transcript levels in 7 of 11 urothelial carcinoma patients. Moreover, reciprocal shifts were observed after treatment of UROtsa cells with HERV-Ec1 and PLA2G4A-directed siRNAs or 5-aza-2'-deoxycytidine (aza-dC) pointing to an antagonistic regulation of PLA2G4A and HERV-Ec1 transcription in human urothelial cells. We suggest that transcription of HERV-Ec1 contributes to fine tuning of cPLA2 expression, thereby facilitating tumorigenesis.
    PLoS ONE 11/2012; 7(11):e49341. DOI:10.1371/journal.pone.0049341 · 3.23 Impact Factor
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