Human endogenous retrovirus np9 gene is over expressed in chronic lymphocytic leukemia patients

Fischer, Sabrina; Echeverría, Natalia; Moratorio, Gonzalo; Landoni, Ana Inés; Dighiero, G; Cristina, Juan; Oppezzo, Pablo; Moreno, Pilar

doi:10.1016/j.lrr.2014.06.005

Cited by 31 publications

(31 citation statements)

References 10 publications

(14 reference statements)

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“…HERV-K is thought to be transcriptionally silent in normal cells, and becomes active after malignant transformation (8,11), except in the case of brain tumors (12). Increased expression of HERV-K has been detected in human cancers (8,13–21), and transcripts of HERVs have been detected by many independent investigators in various types of cancer that include breast cancer (8,22,23), ovarian cancer (24, 25), lymphoma (26,27), melanoma (11,28–32), germ line tumors (33–35), and prostate cancer (5, 36). Our laboratory showed that the HERV-K family is active and overexpressed in breast cancer (2,23,37–40): HERV-K expression was detected in 45% to 93% of primary breast tumors (N=479), and a higher rate of lymph node metastasis was associated with HERV-K-positive compared with HERV-K-negative tumors.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth

Radvanyi

Yin

et al. 2017

Clinical Cancer Research

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Purpose We investigated the role of the human endogenous retrovirus type K (HERV-K) envelope (env) gene in pancreatic cancer (PC). Experimental Design shRNA was employed to knockdown (KD) the expression of HERV-K in PC cells. Results HERV-K env expression was detected in seven PC cell lines and in 80% of PC patient biopsies, but not in two normal pancreatic cell lines or uninvolved normal tissues. A new HERV-K splice variant was discovered in several PC cell lines. RT activity and virus-like particles were observed in culture media supernatant obtained from Panc-1 and Panc-2 cells. HERV-K viral RNA levels and anti-HERV-K antibody titers were significantly higher in PC patient sera (N=106) than in normal donor sera (N=40). Importantly, the in vitro and in vivo growth rates of three PC cell lines were significantly reduced after HERV-K KD by shRNA targeting HERV-K env, and there was reduced metastasis to lung after treatment. RNA-seq results revealed changes in gene expression after HERV-K env KD, including RAS and TP53. Furthermore, downregulation of HERV-K Env protein expression by shRNA also resulted in decreased expression of RAS, p-ERK, p-RSK, and p-AKT in several PC cells or tumors. Conclusion These results demonstrate that HERV-K influences signal transduction via the RAS-ERK-RSK pathway in PC. Our data highlight the potentially important role of HERV-K in tumorigenesis and progression of PC, and indicate that HERV-K viral proteins may be attractive biomarkers and/or tumor-associated antigens, as well as potentially useful targets for detection, diagnosis and immunotherapy of PC.

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Section: Introductionmentioning

confidence: 99%

Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth

Radvanyi

Yin

et al. 2017

Clinical Cancer Research

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“…Chronic lymphocytic leukemia (CLL) cells demonstrate increased transcription of auxillary HERV-K/HML-2 (ERVK) gene Np9, which was previously published as possible oncogene [211]. Indeed, silencing of Np9 inhibits the growth of myeloid and lymphoblastic leukemic cells, whereas its overexpression promotes the growth in vitro and in vivo.…”

Section: Cancermentioning

confidence: 99%

Molecular functions of human endogenous retroviruses in health and disease

Suntsova

Garazha

Ivanova

et al. 2015

Cell. Mol. Life Sci.

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Human endogenous retroviruses (HERVs) and related genetic elements form 504 distinct families and occupy ~8% of human genome. Recent success of high-throughput experimental technologies facilitated understanding functional impact of HERVs for molecular machinery of human cells. HERVs encode active retroviral proteins, which may exert important physiological functions in the body, but also may be involved in the progression of cancer and numerous human autoimmune, neurological and infectious diseases. The spectrum of related malignancies includes, but not limits to, multiple sclerosis, psoriasis, lupus, schizophrenia, multiple cancer types and HIV. In addition, HERVs regulate expression of the neighboring host genes and modify genomic regulatory landscape, e.g., by providing regulatory modules like transcription factor binding sites (TFBS). Indeed, recent bioinformatic profiling identified ~110,000 regulatory active HERV elements, which formed at least ~320,000 human TFBS. These and other peculiarities of HERVs might have played an important role in human evolution and speciation. In this paper, we focus on the current progress in understanding of normal and pathological molecular niches of HERVs, on their implications in human evolution, normal physiology and disease. We also review the available databases dealing with various aspects of HERV genetics.

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“…It would also be interesting to further explore the scope of np9 and rec upregulation in even more cancers. Although we used RNA-seq files from 15 different types of cancer, there are more cancer types reported in the literature to overexpress HERVs: colorectal cancer [37] , chronic lymphocytic leukaemia (CLL) [38] , and Burkitt's lymphoma [39] . Further research could also be performed to characterise the broad network that indicates how Np9 and Rec proteins interact with effectors in the MAPK/Akt/NOTCH signalling cascade that ultimately leads to cell survival and proliferation, specific to the cancers they are upregulated in.…”

Section: Discussionmentioning

confidence: 99%

Targeting endogenous retrovirus gene transcription in human cancers

Lin

Marchi

et al. 2018

Preprint

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Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections that make up to 8% of the human genome. Although these elements are mostly fragmented and inactive, many proviruses belonging to the HERV-K (HML-2) family, the only lineage still proliferating in the genome after the human-chimpanzee split, have intact open reading frames, some encoding for accessory genes called np9 and rec that interact with oncogenic pathways. Many studies have established that the transient expression of ERVs are in both stem cells and cancers results in aberrant self-renewal and uncontrolled proliferation.The wealth of high-quality genomic and transcriptomic Illumina sequence data available from The Cancer Genome Atlas (TCGA) that are sequenced from a diversity of different tumour types makes it a valuable resource in cancer research. However, there is currently no universal computational method for inferring expression of specific repetitive elements from RNA-seq data, such as genes encoded by HERV-K (HML-2).This study presents a novel and a highly specific pipeline that is able to capture and measure transcription of np9 and rec encoded by proviruses that share great sequence similarity, and are transcribed at very low levels. We show by using our novel methodology that np9 and rec are overexpressed in breast cancer, germ cell tumours, skin melanoma, lymphoma, ovarian cancer, and prostate cancer compared to non-diseased tissues. We also show that np9 and rec are specifically expressed in the 8 and 16-cell stage in human preimplantation embryos.

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Human endogenous retrovirus np9 gene is over expressed in chronic lymphocytic leukemia patients

Cited by 31 publications

References 10 publications

Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth

Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth

Molecular functions of human endogenous retroviruses in health and disease

Targeting endogenous retrovirus gene transcription in human cancers

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