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Journal of Cancer Research and Clinical Oncology

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Open Access 01-03-2020 | Human Cytomegalovirus | Original Article – Cancer Research

Overexpression of the human cytomegalovirus UL111A is correlated with favorable survival of patients with gastric cancer and changes T-cell infiltration and suppresses carcinogenesis

Authors: Xin Liu, Kangming Lin, Xielin Huang, Wangkai Xie, Dan Xiang, Ning Ding, Changyuan Hu, Xian Shen, Xiangyang Xue, Yingpeng Huang

Published in: Journal of Cancer Research and Clinical Oncology | Issue 3/2020

Abstract

Purpose

We previously found that human cytomegalovirus (HCMV) infection is associated with gastric cancer (GC) development. UL111A plays a role during HCMV productive or latent infection. However, UL111A expression profiles in GC tissues and their relationship with this disease are unknown.

Methods

PCR and nested RT-PCR were performed to verify UL111A expression in 71 GC tissues and its transcripts in 16 UL111A-positive GC samples. UL111A expression levels in GC patients were evaluated by immunohistochemistry on a tissue microarray for 620 GC patients. The correlations among UL111A expression levels, clinicopathological characteristics, and prognosis were analyzed. Further, the effects of overexpression of latency-associated viral interleukin-10 (LAcmvIL-10) and cmvIL-10 on GC cell proliferation, colony formation, migration, and invasion were assessed.

Results

The UL111A detection rate in GC tissues was 32.4% (23/71) and that of its mRNA expression was 68.75% (11/16). High expression of UL111A was also related to better overall and disease-free survival in GC patients. GC patients with TNM II/III stage expressing higher UL111A levels might benefit from adjuvant chemotherapy (ACT) after surgery. Moreover, high UL111A expression was also associated with increased CD4+ , CD8+ T-lymphocyte and Foxp3+ T-cell infiltration. In vitro assays further demonstrated that LAcmvIL-10 and cmvIL-10 overexpression inhibits GC cell line proliferation, colony formation, migration, and invasion.

Conclusions

High UL111A expression changes the number of infiltrating T cells and is associated with favorable survival. Therefore, UL111A could be used as an independent prognostic biomarker and might be a potential therapeutic target for GC.

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Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang X-S et al (2015) Global surveillance of cancer survival 1995–2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet 385(9972):977–1010PubMed

Baryawno N, Rahbar A, Wolmer-Solberg N, Taher C, Odeberg J, Darabi A et al (2011) Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J Clin Investig 121(10):4043–4055PubMedPubMedCentral

Bishop RK, Oseguera CAV, Spencer J (2015) Human cytomegalovirus interleukin-10 promotes proliferation and migration of MCF-7 breast cancer cells. Cancer Cell Microenviron 2(1):261–267

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424PubMed

Chee MS, Bankier AT, Beck S, Bohni R, Brown CM, Cerny R et al (1989) Analysis of the protein-coding content of the sequence of human cytomegalovirus strain AD169. Microbiol Immunol 154(103):125

Cheung AKL, Gottlieb DJ, Plachter B, Pepperl-Klindworth S, Avdic S, Cunningham AL et al (2009) The role of the human cytomegalovirus UL111A gene in down-regulating CD4+ T-cell recognition of latently infected cells: implications for virus elimination during latency. Blood 114(19):4128–4137PubMed

Cobbs CS, Lualhati H, Minu S, Yancey G, Suman B, King PH et al (2002) Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res 62(12):3347–3350PubMed

Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJH, Nicolson M et al (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355(1):11–20PubMed

Dioverti MV, Razonable RR (2016) Cytomegalovirus. Microbiol Spectr 4(4):DMIH2-0022-2015. https://doi.org/10.1128/microbiolspec.DMIH2-0022-2015 CrossRef

Dziurzynski K, Wei J, Qiao W, Hatiboglu MA, Kong LY, Wu A et al (2011) Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype. Clin Cancer Res 17(14):4642–4649PubMedPubMedCentral

Feichtenbeiner A, Haas M, Büttner M, Grabenbauer GG, Fietkau R, Distel LV (2013) Critical role of spatial interaction between CD8+ and Foxp3+ cells in human gastric cancer: the distance matters. Cancer Immunol Immunother 63(2):111–119PubMed

Fridman WH, Zitvogel L, Sautès-Fridman C, Kroemer G (2017) The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol 14(12):717–734PubMed

Fu M, Gao Y, Zhou Q, Zhang Q, Peng Y, Tian K et al (2014) Human cytomegalovirus latent infection alters the expression of cellular and viral microRNA. Gene 536(2):272–278PubMed

Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022PubMedPubMedCentral

Harkins L, Volk AL, Samanta M, Mikolaenko I, Britt WJ, Bland KI et al (2002) Specific localisation of human cytomegalovirus nucleic acids and proteins in human colorectal cancer. Lancet 360(9345):1557–1563PubMed

Harkins LE, Matlaf LA, Soroceanu L, Klemm K, Britt WJ, Wang W et al (2010) Detection of human cytomegalovirus in normal and neoplastic breast epithelium. Herpesviridae 1(1):1–10

Herbein G (2018) The human cytomegalovirus, from oncomodulation to oncogenesis. Viruses 10(8):408PubMedCentral

Holder KA, Grant MD (2019) Human cytomegalovirus IL-10 augments NK cell cytotoxicity. J Leukoc Biol 106(2):447–454PubMed

Jenkins C, Abendroth A, Slobedman B (2004) A novel viral transcript with homology to human interleukin-10 is expressed during latent human cytomegalovirus infection. J Virol 78(3):1440–1447PubMedPubMedCentral

Jenkins C, Garcia W, Abendroth A, Slobedman B (2008a) Expression of a human cytomegalovirus latency-associated homolog of interleukin-10 during the productive phase of infection. Virology 370(2):285–294PubMed

Jenkins C, Garcia W, Godwin MJ, Spencer JV, Stern JL, Abendroth A et al (2008b) Immunomodulatory properties of a viral homolog of human interleukin-10 expressed by human cytomegalovirus during the latent phase of infection. J Virol 82(7):3736–3750PubMedPubMedCentral

Jin J, Hu C, Wang P, Chen J, Wu T, Chen W et al (2014) Latent infection of human cytomegalovirus is associated with the development of gastric cancer. Oncol Lett 8(2):898–904PubMedPubMedCentral

Jones BC, Logsdon NJ, Kristopher J, Jennifer C, Barry PA, Walter MR (2002) Crystal structure of human cytomegalovirus IL-10 bound to soluble human IL-10R1. Proc Natl Acad Sci USA 99(14):9404–9409PubMedPubMedCentral

Kotenko SV, Saccani S, Izotova LS, Mirochnitchenko OV, Pestka S (2000) Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc Natl Acad Sci USA 97(4):1695–1700PubMedPubMedCentral

Kumar A, Coquard L, Pasquereau S, Russo L, Valmary-Degano S, Borg C et al (2016) Tumor control by human cytomegalovirus in a murine model of hepatocellular carcinoma. Mol Ther Oncol 3:16012

Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL et al (2008) Prognostic implications of type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 99(10):1704–1711PubMedPubMedCentral

Lee JS, Won HS, Sun DS, Hong JH, Ko YH (2018) Prognostic role of tumor-infiltrating lymphocytes in gastric cancer. Medicine 97(32):e11769PubMedPubMedCentral

Lockridge KM, Zhou SS, Kravitz RH, Johnson JL, Sawai ET, Blewett EL et al (2000) Primate cytomegaloviruses encode and express an IL-10-like protein. Virology 268(2):272–280PubMed

Mari E, Floriani I, Tinazzi A, Buda A, Belfiglio M, Valentini M et al (2000) Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente). Ann Oncol 11(7):837–843PubMed

Mason GM, Poole E, Sissons JGP, Wills MR, Sinclair JH (2012) Human cytomegalovirus latency alters the cellular secretome, inducing cluster of differentiation (CD)4+ T-cell migration and suppression of effector function. Proc Natl Acad Sci 109(36):14538–14543PubMedPubMedCentral

McSharry B, Avdic S, Slobedman B (2012) Human cytomegalovirus encoded homologs of cytokines, chemokines and their receptors: roles in immunomodulation. Viruses 4(11):2448–2470PubMedPubMedCentral

Mehravaran H, Makvandi M, Samarbaf ZA, Neisi N, Kiani H, Radmehr H et al (2017) Association of human cytomegalovirus with Hodgkin’s disease and non-Hodgkin’s lymphomas. Asian Pac J Cancer Prev 18(3):593–597PubMedPubMedCentral

Mossman KL, Lepiller Q, Abbas W, Kumar A, Tripathy MK, Herbein G (2013) HCMV activates the IL-6-JAK-STAT3 axis in HepG2 cells and primary human hepatocytes. PloS One 8(3):e59591

Oberstein A, Shenk T (2017) Cellular responses to human cytomegalovirus infection: induction of a mesenchymal-to-epithelial transition (MET) phenotype. Proc Natl Acad Sci USA 114(39):E8244–E8253PubMedPubMedCentral

Ouyang W, Rutz S, Crellin NK, Valdez PA, Hymowitz SG (2011) Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol 29:71–109PubMed

Poole E, Avdic S, Hodkinson J, Jackson S, Wills M, Slobedman B et al (2014) Latency-associated viral interleukin-10 (IL-10) encoded by human cytomegalovirus modulates cellular IL-10 and CCL8 secretion during latent infection through changes in the cellular microRNA hsa-miR-92a. J Virol 88(24):13947–13955PubMedPubMedCentral

Raftery MJ, Wieland D, Gronewald S, Kraus AA, Giese T, Schönrich G (2004) Shaping phenotype, function, and survival of dendritic cells by cytomegalovirus-encoded IL-10. J Immunol 173(5):3383–3391PubMed

Samanta M, Harkins L, Klemm K, Britt WJ, Cobbs CS (2003) High prevalence of human cytomegalovirus in prostatic intraepithelial neoplasia and prostatic carcinoma. J Urol 170(3):998–1002PubMed

Saraiva M, O’Garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10(3):170–181PubMed

Slobedman B, Barry PA, Spencer JV, Avdic S, Abendroth A (2009) Virus-encoded homologs of cellular interleukin-10 and their control of host immune function. J Virol 83(19):9618–9629PubMedPubMedCentral

Spencer JV (2006) The cytomegalovirus homolog of interleukin-10 requires phosphatidylinositol 3-kinase activity for inhibition of cytokine synthesis in monocytes. J Virol 81(4):2083–2086PubMedPubMedCentral

Spencer JV, Lockridge KM, Barry PA, Lin G, Tsang M, Penfold MET et al (2002) Potent immunosuppressive activities of cytomegalovirus-encoded interleukin-10. J Virol 76(3):1285–1292PubMedPubMedCentral

Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F et al (2005) Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 202(5):673–685PubMedPubMedCentral

Teo WH, Chen H-P, Huang JC, Chan Y-J (2017) Human cytomegalovirus infection enhances cell proliferation, migration and upregulation of EMT markers in colorectal cancer-derived stem cell-like cells. Int J Oncol 51(5):1415–1426PubMedPubMedCentral

Valle Oseguera CA, Spencer JV (2014) cmvIL-10 stimulates the invasive potential of MDA-MB-231 breast cancer cells. PloS One 9(2):e88708PubMedPubMedCentral

Xu JF, Zhao ZG, Ye LL, Zhuge W, Han Z, Zhang TM et al (2017) Prognostic significance of Daxx NCR (nuclear/cytoplasmic ratio) in gastric cancer. Cancer Med 6(9):2063–2075PubMedPubMedCentral

Yamamoto-Tabata T, McDonagh S, Chang HT, Fisher S, Pereira L (2004) Human cytomegalovirus interleukin-10 downregulates metalloproteinase activity and impairs endothelial cell migration and placental cytotrophoblast invasiveness in vitro. J Virol 78(6):2831–2840PubMedPubMedCentral

Yi-Ling L, Pei-Ching C, Yixiang W, Mengtao L (2008) Identification of novel viral interleukin-10 isoforms of human cytomegalovirus AD169. Virus Res 131(2):213–223

Young VP, Mariano MC, Tu CC, Allaire KM, Avdic S, Slobedman B et al (2017) Modulation of the host environment by human cytomegalovirus with viral interleukin 10 in peripheral blood. J Infect Dis 215(6):874–882PubMedPubMedCentral

Zhang L, Guo G, Xu J, Sun X, Chen W, Jin J et al (2017) Human cytomegalovirus detection in gastric cancer and its possible association with lymphatic metastasis. Diagn Microbiol Infect Dis 88(1):62–68PubMed

Title: Overexpression of the human cytomegalovirus UL111A is correlated with favorable survival of patients with gastric cancer and changes T-cell infiltration and suppresses carcinogenesis
Authors: Xin Liu
Kangming Lin
Xielin Huang
Wangkai Xie
Dan Xiang
Ning Ding
Changyuan Hu
Xian Shen
Xiangyang Xue
Yingpeng Huang
Publication date: 01-03-2020
Publisher: Springer Berlin Heidelberg
Keywords: Human Cytomegalovirus
Gastric Cancer
Gastric Cancer
Published in: Journal of Cancer Research and Clinical Oncology / Issue 3/2020
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-019-03092-x

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Purpose

Methods

Results

Conclusions

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