23 de maio de 2019

[VC Feed] "Intermittent abortive reactivation of Epstein-Barr virus during the progression of nasopharyngeal cancer as indicated by elevated antibody levels."

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Intermittent abortive reactivation of Epstein-Barr virus during the progression of nasopharyngeal cancer as indicated by elevated antibody levels.
Oral Oncol. 2019 Jun;93:85-90
Authors: Guo X, Li T, Li F, Xu Y, Wang H, Cheng W, Tang J, Zhou G, Chen H, Ng M, Ji M, Ge S, Xia N
The development of nasopharyngeal carcinoma (NPC), a common cancer in Southeastern Asia, is closely associated with Epstein-Barr virus (EBV) infection; however, the aetiological role of EBV in NPC pathogenesis remains enigmatic. The life cycle of EBV in NPC patients is defined as latency II, while the antibodies specific to lytic phase proteins, as well as lytic genes, were highly expressed in NPC patients. The correlation between antibody levels and the progression of NPC has been reported in some studies; however, most of these studies focused on IgA antibodies, and the results in different articles were not consistent. In this study, we concurrently determined the levels of IgA and IgG antibodies specific to six purified recombinant EBV antigens associated with different replication statuses of EBV: EBNA1 associated with latency II; the non-structural antigens Zta, TK, EA-D and EA-R associated with immediate-early and early lytic phases; and the EBV matrix protein VCA p18, which is involved in late lytic phase. Levels of antibodies specific to immediate-early and early antigens were correlated with the tumour progression, especially tumour size. The levels of antibodies specific to some lytic phase antigens were also correlated with lymph node inclusion and metastasis. However, the antibody specific to the latency II antigen EBNA1 was not correlated with either tumour size or metastasis. Consistent with previous transcriptome studies, the results suggested both the expression of lytic phase genes at the protein level and the intermittent reactivation of EBV in NPC patients.

PMID: 31109701 [PubMed - in process]

May 22, 2019 at 11:07AM

20 de outubro de 2018

"Tracking EBV-encoded RNAs (EBERs) from the nucleus to the excreted exosomes of B-lymphocytes."

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Tracking EBV-encoded RNAs (EBERs) from the nucleus to the excreted exosomes of B-lymphocytes.

Sci Rep. 2018 Oct 18;8(1):15438

Authors: Ahmed W, Tariq S, Khan G

Epstein-Barr virus-encoded RNAs (EBER1 and EBER2) are two highly abundant, non-protein coding RNAs consistently expressed in all EBV infected cells, but their function remains poorly understood. Conventional in situ hybridization studies have indicated that these RNAs are present exclusively in the nucleus. We have recently demonstrated that EBERs can be excreted from infected cells via exosomes. However, the details of the steps involved in their excretion remain unknown. In this study, we aimed to directly track the journey of EBERs from the nucleus to the excretory exosomes of EBV immortalized B-lymphocytes. Using a combination of molecular and novel immuno-gold labelled electron microscopy (EM) based techniques, we demonstrate the presence of EBERs, not only in the nucleus, but also in the cytoplasm of EBV infected B cell lines. EBERs were also seen in exosomes shed from infected cells along with the EBER binding protein La. Our results show, for the first time, that at least a proportion of EBERs are transported from the nucleus to the cytoplasm where they appear to be loaded into multi-vesicular bodies for eventual excretion via exosomes.

PMID: 30337610 [PubMed - in process]

October 20, 2018 at 10:05AM

19 de outubro de 2018

"Overexpression of cellular telomerase RNA enhances virus-induced cancer formation"

  1. 1.

    Blackburn EH. Telomere states and cell fates. Nature. 2000;408:53–6.

  2. 2.

    Collins K. Physiological assembly and activity of human telomerase complexes. Mech Ageing Dev. 2008;129:91–8.

  3. 3.

    Autexier C, Lue NF. The structure and function of telomerase reverse transcriptase. Annu Rev Biochem. 2006;75:493–517.

  4. 4.

    Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266:2011–5.

  5. 5.

    Martin-Rivera L, Blasco MA. Identification of functional domains and dominant negative mutations in vertebrate telomerase RNA using an in vivo reconstitution system. J Biol Chem. 2001;276:5856–65.

  6. 6.

    Chen JL, Blasco MA, Greider CW. Secondary structure of vertebrate telomerase RNA. Cell. 2000;100:503–14.

  7. 7.

    Cao Y, Bryan TM, Reddel RR. Increased copy number of the TERT and TERC telomerase subunit genes in cancer cells. Cancer Sci. 2008;99:1092–9.

  8. 8.

    Baena-Del Valle JA, Zheng Q, Esopi DM, Rubenstein M, Hubbard GK, Moncaliano MC, et al. MYC drives overexpression of telomerase RNA (hTR/TERC) in prostate cancer. J Pathol. 2018;244:11–24.

  9. 9.

    Penzo M, Ludovini V, Trere D, Siggillino A, Vannucci J, Bellezza G, et al. Dyskerin and TERC expression may condition survival in lung cancer patients. Oncotarget. 2015;6:21755–60.

  10. 10.

    Li L, Jiang W, Zeng SY, Li L. Prospective study of hTERC gene detection by fluorescence in situ hybridization (FISH) in cervical intraepithelial neoplasia 1 natural prognosis. Eur J Gynaecol Oncol. 2014;35:289–91.

  11. 11.

    Nowak T, Januszkiewicz D, Zawada M, Pernak M, Lewandowski K, Rembowska J, et al. Amplification of hTERT and hTERC genes in leukemic cells with high expression and activity of telomerase. Oncol Rep. 2006;16:301–5.

  12. 12.

    Gazzaniga FS, Blackburn EH. An antiapoptotic role for telomerase RNA in human immune cells independent of telomere integrity or telomerase enzymatic activity. Blood. 2014;124:3675–84.

  13. 13.

    Rumin Wen JL, Li Wang, Yang Wenfa, Mao Lijun, Zheng Junnian. Attenuation of telomerase activity by siRNA targeted telomerase RNA leads to apoptosis and inhibition of proliferation in human renal carcinoma cells. Chinese. J Clin Oncol. 2006;3:326–31.

  14. 14.

    Osterrieder N, Kamil JP, Schumacher D, Tischer BK, Trapp S. Marek's disease virus: from miasma to model. Nat Rev Microbiol. 2006;4:283–94.

  15. 15.

    Trapp S, Parcells MS, Kamil JP, Schumacher D, Tischer BK, Kumar PM, et al. A virus-encoded telomerase RNA promotes malignant T cell lymphomagenesis. J Exp Med. 2006;203:1307–17.

  16. 16.

    Fragnet L, Blasco MA, Klapper W, Rasschaert D. The RNA subunit of telomerase is encoded by Marek's disease virus. J Virol. 2003;77:5985–96.

  17. 17.

    Fragnet L, Kut E, Rasschaert D. Comparative functional study of the viral telomerase RNA based on natural mutations. J Biol Chem. 2005;280:23502–15.

  18. 18.

    Shkreli M, Dambrine G, Soubieux D, Kut E, Rasschaert D. Involvement of the oncoprotein c-Myc in viral telomerase RNA gene regulation during Marek's disease virus-induced lymphomagenesis. J Virol. 2007;81:4848–57.

  19. 19.

    Chbab N, Egerer A, Veiga I, Jarosinski KW, Osterrieder N. Viral control of vTR expression is critical for efficient formation and dissemination of lymphoma induced by Marek's disease virus (MDV). Vet Res. 2010;41:56.

  20. 20.

    Mason M, Schuller A, Skordalakes E. Telomerase structure function. Curr Opin Struct Biol. 2011;21:92–100.

  21. 21.

    Wyatt HDM, West SC, Beattie TL. InTERTpreting telomerase structure and function. Nucleic Acids Res. 2010;38:5609–22.

  22. 22.

    Kaufer BB, Trapp S, Jarosinski KW, Osterrieder N. Herpesvirus telomerase RNA(vTR)-dependent lymphoma formation does not require interaction of vTR with telomerase reverse transcriptase (TERT). PLoS Pathog. 2010;6:e1001073.

  23. 23.

    Kheimar A, Kaufer BB. Epstein-Barr virus-encoded RNAs (EBERs) complement the loss of Herpesvirus telomerase RNA (vTR) in virus-induced tumor formation. Sci Rep. 2018;8:209.

  24. 24.

    Akıncılar SC, Low KC, Liu CY, Yan TD, Oji A, Ikawa M, et al. Quantitative assessment of telomerase components in cancer cell lines. FEBS Lett. 2015;589:974–84.

  25. 25.

    Koh CM, Khattar E, Leow SC, Liu CY, Muller J, Ang WX, et al. Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity. J Clin Invest. 2015;125:2109–22.

  26. 26.

    Khattar E, Kumar P, Liu CY, Akincilar SC, Raju A, Lakshmanan M, et al. Telomerase reverse transcriptase promotes cancer cell proliferation by augmenting tRNA expression. J Clin Invest. 2016;126:4045–60.

  27. 27.

    Murre C. Ribosomal proteins and the control of alphabeta T lineage development. Immunity. 2007;26:751–2.

  28. 28.

    Anderson SJ, Lauritsen JP, Hartman MG, Foushee AM, Lefebvre JM, Shinton SA, et al. Ablation of ribosomal protein L22 selectively impairs alphabeta T cell development by activation of a p53-dependent checkpoint. Immunity. 2007;26:759–72.

  29. 29.

    Rao S, Cai KQ, Stadanlick JE, Greenberg-Kushnir N, Solanki-Patel N, Lee SY, et al. Ribosomal protein Rpl22 controls the dissemination of T-cell lymphoma. Cancer Res. 2016;76:3387–96.

  30. 30.

    Rao S, Lee SY, Gutierrez A, Perrigoue J, Thapa RJ, Tu Z, et al. Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B. Blood. 2012;120:3764–73.

  31. 31.

    Le S, Sternglanz R, Greider CW. Identification of two RNA-binding proteins associated with human telomerase RNA. Mol Biol Cell. 2000;11:999–1010.

  32. 32.

    Ghosh A, Saginc G, Leow SC, Khattar E, Shin EM, Yan TD, et al. Telomerase directly regulates NF-kappaB-dependent transcription. Nat Cell Biol. 2012;14:1270–81.

  33. 33.

    Tischer BK, Smith GA, Osterrieder N. En passant mutagenesis: a two step markerless red recombination system. Methods Mol Biol. 2010;634:421–30.

  34. 34.

    Engel AT, Selvaraj RK, Kamil JP, Osterrieder N, Kaufer BB. Marek's disease viral interleukin-8 (vIL-8)promotes lymphoma formation through targeted recruitment of B-cells and CD4+ CD25+ T-cells. J Virol.2012;86:8536–8545.

  35. 35.

    Tischer BK, Kaufer BB. Viral bacterial artificial chromosomes: generation, mutagenesis, and removal of mini-F sequences. J Biomed Biotechnol. 2012;2012:472537.

  36. 36.

    Tischer BK, von Einem J, Kaufer B, Osterrieder N. Two-step red-mediated recombination for versatile high-efficiency markerless DNA manipulation in Escherichia coli. Biotechniques. 2006;40:191–7.

  37. 37.

    Jarosinski KW, Margulis NG, Kamil JP, Spatz SJ, Nair VK, Osterrieder N. Horizontal transmission of Marek's disease virus requires US2, the UL13 protein kinase, and gC. J Virol. 2007;81:10575–87.

  38. 38.

    Schumacher D, Tischer BK, Trapp S, Osterrieder N. The protein encoded by the US3 orthologue of Marek's disease virus is required for efficient de-envelopment of perinuclear virions and involved in actin stress fiber breakdown. J Virol. 2005;79:3987–97.

  39. 39.

    Jarosinski K, Kattenhorn L, Kaufer B, Ploegh H, Osterrieder N. A herpesvirus ubiquitin-specific protease is critical for efficient T cell lymphoma formation. Proc Natl Acad Sci USA. 2007;104:20025–30.

  40. 40.

    Jarosinski KW, Osterrieder N, Nair VK, Schat KA. Attenuation of Marek's disease virus by deletion of open reading frame RLORF4 but not RLORF5a. J Virol. 2005;79:11647–59.

  41. 41.

    Kaufer BB, Jarosinski KW, Osterrieder N. Herpesvirus telomeric repeats facilitate genomic integration into host telomeres and mobilization of viral DNA during reactivation. J Exp Med. 2011;208:605–15.

October 19, 2018 at 11:31AM

18 de outubro de 2018

"Zebrafish: Speeding Up the Cancer Drug Discovery Process."

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Zebrafish: Speeding Up the Cancer Drug Discovery Process.

Cancer Res. 2018 Oct 16;:

Authors: Letrado P, de Miguel I, Lamberto I, Díez-Martínez R, Oyarzabal J

Zebrafish (Danio rerio) is an ideal in vivo model to study a wide variety of human cancer types. In this review, we provide a comprehensive overview of zebrafish in the cancer drug discovery process, from (i) approaches to induce malignant tumors, (ii) techniques to monitor cancer progression, and (iii) strategies for compound administration to (iv) a compilation of the 355 existing case studies showing the impact of zebrafish models on cancer drug discovery, which cover a broad scope of scenarios. Finally, based on the current state-of-the-art analysis, this review presents some highlights about future directions using zebrafish in cancer drug discovery and the potential of this model as a prognostic tool in prospective clinical studies. Cancer Res; 78(21); 1-11. ©2018 AACR.

PMID: 30327381 [PubMed - as supplied by publisher]

October 18, 2018 at 12:50PM

17 de outubro de 2018

"EBV reduces autophagy, intracellular ROS and mitochondria to impair monocyte survival and differentiation."

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EBV reduces autophagy, intracellular ROS and mitochondria to impair monocyte survival and differentiation.

Autophagy. 2018 Oct 16;:

Authors: Gilardini Montani MS, Santarelli R, Granato M, Gonnella R, Torrisi MR, Faggioni A, Cirone M

EBV has been reported to impair monocyte in vitro differentiation into dendritic cells (DCs) and reduce cell survival. In this study, we added another layer of knowledge to this topic and showed that these effects correlated with macroautophagy/autophagy, ROS and mitochondrial biogenesis reduction. Of note, autophagy and ROS, although strongly interconnected, have been separately reported to be induced by CSF2/GM-CSF (colony stimulating factor 2) and required for CSF2-IL4-driven monocyte in vitro differentiation into DCs. We show that EBV infects monocytes and initiates a feedback loop in which, by inhibiting autophagy, reduces ROS and through ROS reduction negatively influences autophagy. Mechanistically, autophagy reduction correlated with the downregulation of RAB7 and ATG5 expression and STAT3 activation, leading to the accumulation of SQSTM1/p62. The latter activated the SQSTM1-KEAP1- NFE2L2 axis and upregulated the anti-oxidant response, reducing ROS and further inhibiting autophagy. ROS decrease correlated also with the reduction of mitochondria, the main source of intracellular ROS, achieved by the downregulation of NRF1 and TFAM, mitochondrial biogenesis transcription factors. Interestingly, mitochondria supply membranes and ATP required for autophagy execution, thus their reduction may further reduce autophagy in EBV-infected monocytes. In conclusion, this study shows for the first time that the interconnected reduction of autophagy, intracellular ROS and mitochondria mediated by EBV switches monocyte differentiation into apoptosis, giving new insights into the mechanisms through which this virus reduces immune surveillance.

PMID: 30324853 [PubMed - as supplied by publisher]

October 17, 2018 at 08:51AM