Chronic hepatitis C virus infection (C-HC) is associated with higher mortality arising from hepatic and extrahepatic disease. This may be due to accelerated biological aging; however, studies in C-HC have thus far been based solely on telomere length as a biomarker of aging (BoA). In this study, we have evaluated CDKN2 locus transcripts as alternative BoAs in C-HC. Our results suggest that C-HC induces non-cell-autonomous senescence and accelerates biological aging. The CDKN2 locus may provide a link between C-HC and increased susceptibility to age-associated diseases and provides novel biomarkers for assessing its impact on aging processes in man

Barclay, Stephen

McGuinness, Dagmara

McLauchlan, John

Mills, Peter R.

Patel, Arvind H.

Robinson, Mark W.

Shiels, Paul G.

Swann, Rachael

Aging Cell

English

Enlighten

    Robinson, M.W., McGuinness, D., Swann, R., Barclay, S., Mills, P.R., Patel, A. H., McLauchlan, J., and Shiels, P.G. (2013) Non cell autonomous increase in the expression of CDKN2 transcripts is associated with the progression of chronic hepatitis C disease. Aging Cell, 12 (6). pp. 1141-1143. ISSN 1474-9718   Copyright © 2013 The Authors    http://eprints.gla.ac.uk/81793    Deposited on:  04 March 2014                         Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk SHORT TAKENon cell autonomous upregulation of CDKN2 transcriptionlinked to progression of chronic hepatitis C diseaseMark W. Robinson,1* Dagmara McGuinness,2* RachaelSwann,1,3 Stephen Barclay,4 Peter R. Mills,3 Arvind H. Patel,1John McLauchlan1† and Paul G. Shiels2†1MRC – University of Glasgow Centre for Virus Research, Glasgow, UK2Section of Epigenetics, Institute of Cancer Sciences, MVLS, University ofGlasgow, Glasgow, UK3Gartnavel General Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK4Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde, Glasgow, UKSummaryChronic hepatitis C virus infection (C-HC) is associated with highermortality arising from hepatic and extrahepatic disease. This maybe due to accelerated biological aging; however, studies in C-HChave thus far been based solely on telomere length as abiomarker of aging (BoA). In this study, we have evaluatedCDKN2 locus transcripts as alternative BoAs in C-HC. Our resultssuggest that C-HC induces non-cell-autonomous senescence andaccelerates biological aging. The CDKN2 locus may provide a linkbetween C-HC and increased susceptibility to age-associateddiseases and provides novel biomarkers for assessing its impacton aging processes in man.Key words: biological aging; CDKN2 locus; chronic HCVinfection; telomere length.IntroductionAcute hepatitis C virus (HCV) infection is largely asymptomatic, andchronic infection is often identified years later, following the develop-ment of liver disease (Seeff, 2009). Due to the cumulative nature offibrosis and cirrhosis, HCV-related morbidity and mortality increase withage (Grebely & Dore, 2011). Chronic HCV infection (C-HC) is alsoassociated with increased risk of extrahepatic diseases in the absence ofother comorbidities or risk behaviours (Grebely & Dore, 2011; Lee et al.,2012), suggesting that C-HC alters the capacity of an individual to resistthe development of disease. It has been postulated that individuals withC-HC undergo premature biological aging, with increased cellularsenescence, coincident with chronic inflammation and oxidative stress(Hoare et al., 2010a), although the nature of any mechanistic linkremains to be determined. This hypothesis parallels observations inhuman immunodeficiency virus (HIV)-infected patients who have ahigher than expected risk of complications typically associated withaging (Deeks, 2011). While an independent association between age-related diseases and HIV-induced aging has not been defined, theelevated risk is consistent with the observation that infection increasesbiomarkers associated with senescence commonly found in elderlypopulations (Deeks, 2011).How biomarkers of aging (BoA) differ between HCV-infected anduninfected patients remains to be conclusively determined. Non-cell-autonomous senescence as a consequence of viral infection could explainthe greater risk of age-related diseases in patients with C-HC. In patientswith C-HC, shorter telomere lengths are found in circulating leucocytes(Kitay-Cohen et al., 2008), T cells (Hoare et al., 2010b) and liver biopsies(Sekoguchi et al., 2007). However, recent studies highlight methodolog-ical issues surrounding measurement of telomere length (Shiels, 2010;Aviv et al., 2011). The cyclin-dependent kinase inhibitor (CDKN)2A hasbeen validated as an alternative BoA, which may represent a morereproducible measure of biological age (Shiels, 2010). Elevated CDKN2Atranscription occurs with increasing age in both peripheral bloodleucocytes (Liu et al., 2009) and solid organs, where it correlates withorgan function (Koppelstaetter et al., 2008). In this study, we investi-gated the correlation between C-HC and BoAs including telomere length,CDKN2A and the related transcripts CDKN2B and ARF. We hypothesizethat viral persistence induces non-cell-autonomous senescence, whichmay accelerate development of age-related diseases.Study participants were recruited into two groups: healthy controls(n = 24) who were negative for HCV-specific antibodies and patientswith C-HC (n = 43) who were positive for both HCV-specific antibodiesand viral RNA (Table S1). No significant differences were observed ingender, ethnicity, age or body mass index of healthy controls andpatients with C-HC. Alanine transaminase values were significantlyhigher in the C-HC group compared with controls consistent with thepresence of liver disease.Higher expression of CDKN2A (P = 0.0002), ARF (P = 0.0008) andCDKN2B (P = 0.0002) was observed in peripheral blood mononuclearcells (PBMCs) of patients with C-HC, compared with healthy controls(Fig. 1A and B, and Table S1). Elevated expression of CDKN2Atranscripts coincided with increased p16 protein levels in PBMCs frompatients with C-HC (Fig.S1). By contrast, no statistical difference wasfound in relative telomere length (P = 0.2176, Fig. 1C). To investigatewhether these biomarkers were altered due to disease state or viralgenotype, the C-HC group was divided according to the presence orabsence of liver cirrhosis (measured by transient elastography) and viralgenotype (either genotype 1 or genotype 3). In patients with livercirrhosis (n = 14), expression of CDKN2A and ARF was significantlyhigher compared with those without liver cirrhosis (n = 27) (Fig. 2A).CDKN2B expression and p16 protein levels showed the same trendalthough they failed to reach statistical significance (Fig. 2A andFig. S1C). No significant differences were noted in relative telomereCorrespondenceJohn McLauchlan, MRC-University of Glasgow Centre for Virus Research, 8 ChurchStreet, Glasgow G11 5JR, Tel.: +0141 330 4028; fax: +0141 330 4029;e-mail: john.mclauchlan@glasgow.ac.ukPaul Gerard Shiels, University of Glasgow College of Medical, Veterinary & LifeSciences, Institute of Cancer Sciences, McGregor Building, Level 2 WesternInfirmary Glasgow, G11 6NT, Glasgow. Tel./fax: +0141 211 2138;e-mail: Paul.Shiels@glasgow.ac.uk*Shared first authors.†Shared last authors.This research was supported by funding from the UK Medical Research Council(MRC).Accepted for publication 16 June 2013ª 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use,distribution and reproduction in any medium, provided the original work is properly cited.1141Aging Cell (2013) 12, pp1141–1143 Doi: 10.1111/acel.12125Aging Celllength between C-HC patients with or without liver cirrhosis (Fig. 2B).Separating the patients with C-HC according to viral genotype (geno-type 1 (n = 23) and genotype 3 (n = 18)) showed no difference intelomere length or expression of CDKN2 locus transcripts (Supplemen-tary Fig. 2).Elevated transcription of CDKN2A, ARF and CDKN2B in PBMC isconsistent with C-HC-associated non-cell-autonomous senescence,resulting in increased biological aging in infected patients. This findingsupports reports linking accelerated aging and HCV (Kitay-Cohen et al.,2008; Hoare et al., 2010b) and implies that C-HC indirectly drives thedevelopment of senescence in PBMCs. While a trend towards decreasingtelomere length in C-HC patients with cirrhosis was seen, unlike previousfindings, HCV infection was not associated with a significant decrease intelomere length (Kitay-Cohen et al., 2008; Hoare et al., 2010b). Thisdifference is likely due to the use of different techniques and highlightsthe issues surrounding the use of any single measure as a definitive BoA(Shiels, 2010; Aviv et al., 2011).Our findings indicate that increased CDKN2 locus transcription inPBMCs is a surrogate marker for the degree of liver damage, with thehighest expression levels of these BoAs noted in C-HC patients withcirrhosis. Whether this is due solely to the progression of HCV infection oralternatively whether liver cirrhosis independently induces senescence isunknown. Elevated liver fibrosis and cirrhosis have been reported in micewhere the p53-dependent senescence programme had been ablated(Lujambio et al., 2013). In this study, the inductionof p53-dependent non-cell-autonomous senescence acts tomaintain organ integrity and suppressliver damage; our findings are consistent with this model and providebiomarkers for exploring this in in vivo human studies.The observation of altered CDKN2 locus transcription, in associationwith HCV infection, is consistent with non-cell-autonomous senescence.Our study provides biomarkers for addressing the role of senescence inC-HC infection and may aid patient management as prognostic tools forthe progression of liver disease and the development of extrahepaticcomplications.CDKN2BCDKN2AARF−2 0Log FoldChange2C CCCCC CC C CH C C CCCCC C C CCCH H H HHHH H H H H H H H H H H H H H HHHH H H H HHHH H H H HHHH H H(A)Healthy controls C-HC patientsFold changeARF CDKN2A CDKN2B02468*** *** ***(B)Telomere length (T/S)0.00.51.01.5(C)4Fig. 1 Expression of CDKN2 locustranscripts and relative telomere length inpatients with C-HC and healthy controls.Heat map (A) and expression profile (B) ofCDKN2 locus transcripts from patients withC-HC (H; n = 41) and healthy controls (C;n = 22). (C) Relative telomere length inwhole blood from patients with C-HC(n = 42) compared with healthy controls(n = 24). Data are presented as mean with95% confidence intervals; ***denotesP < 0.001.Healthy controls C-HC without cirrhosis C-HC with cirrhosisFold changeARF CDKN2A CDKN2B04812************(A) (B)Telomere length (T/S)0.00.51.01.5Fig. 2 Expression of CDKN2 locustranscripts and relative telomere length inC-HC patients with/without liver cirrhosisand healthy controls. (A) Expression ofCDKN2 locus transcripts from C-HCpatients with (n = 14) or without (n = 27)liver cirrhosis compared with healthycontrols. (B) Relative telomere length inwhole blood from C-HC patients with(n = 15) or without (n = 27) liver cirrhosiscompared with healthy controls. Data arepresented as mean with 95% confidenceintervals; *P < 0.05, ***P < 0.001.Accelerated aging during chronic hepatitis C infection, M. W. Robinson et al.1142ª 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.Author contributionsMWR and DM were involved in study design, data analysis and draftingof manuscript; RS, SB and PRM were involved in patient recruitment;AHP, JM and PGS were involved in study design and critical review of themanuscript.DisclosuresAll authors declare no conflict of interests.ReferencesAviv A, Hunt SC, Lin J, Cao X, Kimura M, Blackburn E (2011) Impartial comparativeanalysis of measurement of leukocyte telomere length/DNA content by Southernblots and qPCR. Nucleic Acids Res. 39, e134.Deeks SG (2011) HIV infection, inflammation, immunosenescence, and aging.Annu. Rev. Med. 62, 141–155.Grebely J, Dore GJ (2011) What is killing people with hepatitis C virus infection?Semin. Liver Dis. 31, 331–339.Hoare M, Das T, Alexander G (2010a) Ageing, telomeres, senescence, and liverinjury. J. Hepatol. 53, 950–961.Hoare M, Gelson WT, Das A, Fletcher JM, Davies SE, Curran MD, Vowler SL, MainiMK, Akbar AN, Alexander GJ (2010b) CD4 + T-lymphocyte telomere length isrelated to fibrosis stage, clinical outcome and treatment response in chronichepatitis C virus infection. J. Hepatol. 53, 252–260.Kitay-Cohen Y, Goldberg-Bittman L, Hadary R, Fejgin MD, Amiel A (2008)Telomere length in Hepatitis C. Cancer Genet. Cytogenet. 187, 34–38.Koppelstaetter C, Schratzberger G, Perco P, Hofer J, Mark W, Ollinger R,Oberbauer R, Schwarz C, Mitterbauer C, Kainz A, Karkoszka H, Wiecek A,Mayer B, Mayer G (2008) Markers of cellular senescence in zero hour biopsiespredict outcome in renal transplantation. Aging Cell 7, 491–497.Lee MH, Yang HI, Lu SN, Jen CL, You SL, Wang LY, Wang CH, Chen WJ, Chen CJ(2012) Chronic hepatitis C virus infection increases mortality from hepatic andextrahepatic diseases: a community-based long-term prospective study. J. Infect.Dis. 206, 469–477.Liu Y, Sanoff HK, Cho H, Burd CE, Torrice C, Ibrahim JG, Thomas NE, Sharpless NE(2009) Expression of p16(INK4a) in peripheral blood T-cells is a biomarker ofhuman aging. Aging Cell 8, 439–448.Lujambio A, Akkari L, Simon J, Grace D, Tschaharganeh DF, Bolden JE, Zhao Z,Thapar V, Joyce JA, Krizhanovsky V, Lowe SW (2013) Non-Cell-AutonomousTumor Suppression by p53. Cell 153, 449–460.Seeff LB (2009) The history of the “natural history” of hepatitis C (1968-2009).Liver Int. 29(Suppl 1), 89–99.Sekoguchi S, Nakajima T, Moriguchi M, Jo M, Nishikawa T, Katagishi T, Kimura H,Minami M, Itoh Y, Kagawa K, Tani Y, Okanoue T (2007) Role of cell-cycleturnover and oxidative stress in telomere shortening and cellular senescence inpatients with chronic hepatitis C. J. Gastroenterol. Hepatol. 22, 182–190.Shiels PG (2010) Improving precision in investigating aging: why telomeres cancause problems. J. Gerontol. A Biol. Sci. Med. Sci. 65, 789–791.Supporting InformationAdditional Supporting Information may be found in the online version of thisarticle at the publisher’s web-site.Data S1. Materials and Methods.Fig. S1. CDKN2A/p16 protein expression in PBMC protein extracts.Fig. S2. CDKN2 locus transcript expression with samples grouped by HCVgenotype.Table S1. Participants clinical characteristics.Accelerated aging during chronic hepatitis C infection, M. W. Robinson et al. 1143ª 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Non cell autonomous upregulation of CDKN2 transcription linked to progression of chronic hepatitis C disease

Enlighten: Publications

Mark W. Robinson

Dagmara McGuinness

Rachael Swann

Stephen Barclay

Peter R. Mills

Arvind H. Patel

John McLauchlan

Paul G. Shiels

Crossref

Chronic hepatitis C virus infection (C‐HC) is associated with higher mortality arising from hepatic and extrahepatic disease. This may be due to accelerated biological aging; however, studies in C‐HC have thus far been based solely on telomere length as a biomarker of aging (BoA). In this study, we have evaluated CDKN2 locus transcripts as alternative BoAs in C‐HC. Our results suggest that C‐HC induces non‐cell‐autonomous senescence and accelerates biological aging. The CDKN2 locus may provide a link between C‐HC and increased susceptibility to age‐associated diseases and provides novel biomarkers for assessing its impact on aging processes in man

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Maynooth University ePrints and eTheses Archive

MURAL - Maynooth University Research Archive Library

SHORT TAKENon cell autonomous upregulation of CDKN2 transcriptionlinked to progression of chronic hepatitis C diseaseMark W. Robinson,1* Dagmara McGuinness,2* RachaelSwann,1,3 Stephen Barclay,4 Peter R. Mills,3 Arvind H. Patel,1John McLauchlan1† and Paul G. Shiels2†1MRC – University of Glasgow Centre for Virus Research, Glasgow, UK2Section of Epigenetics, Institute of Cancer Sciences, MVLS, University ofGlasgow, Glasgow, UK3Gartnavel General Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK4Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde, Glasgow, UKSummaryChronic hepatitis C virus infection (C-HC) is associated with highermortality arising from hepatic and extrahepatic disease. This maybe due to accelerated biological aging; however, studies in C-HChave thus far been based solely on telomere length as abiomarker of aging (BoA). In this study, we have evaluatedCDKN2 locus transcripts as alternative BoAs in C-HC. Our resultssuggest that C-HC induces non-cell-autonomous senescence andaccelerates biological aging. The CDKN2 locus may provide a linkbetween C-HC and increased susceptibility to age-associateddiseases and provides novel biomarkers for assessing its impacton aging processes in man.Key words: biological aging; CDKN2 locus; chronic HCVinfection; telomere length.IntroductionAcute hepatitis C virus (HCV) infection is largely asymptomatic, andchronic infection is often identified years later, following the develop-ment of liver disease (Seeff, 2009). Due to the cumulative nature offibrosis and cirrhosis, HCV-related morbidity and mortality increase withage (Grebely & Dore, 2011). Chronic HCV infection (C-HC) is alsoassociated with increased risk of extrahepatic diseases in the absence ofother comorbidities or risk behaviours (Grebely & Dore, 2011; Lee et al.,2012), suggesting that C-HC alters the capacity of an individual to resistthe development of disease. It has been postulated that individuals withC-HC undergo premature biological aging, with increased cellularsenescence, coincident with chronic inflammation and oxidative stress(Hoare et al., 2010a), although the nature of any mechanistic linkremains to be determined. This hypothesis parallels observations inhuman immunodeficiency virus (HIV)-infected patients who have ahigher than expected risk of complications typically associated withaging (Deeks, 2011). While an independent association between age-related diseases and HIV-induced aging has not been defined, theelevated risk is consistent with the observation that infection increasesbiomarkers associated with senescence commonly found in elderlypopulations (Deeks, 2011).How biomarkers of aging (BoA) differ between HCV-infected anduninfected patients remains to be conclusively determined. Non-cell-autonomous senescence as a consequence of viral infection could explainthe greater risk of age-related diseases in patients with C-HC. In patientswith C-HC, shorter telomere lengths are found in circulating leucocytes(Kitay-Cohen et al., 2008), T cells (Hoare et al., 2010b) and liver biopsies(Sekoguchi et al., 2007). However, recent studies highlight methodolog-ical issues surrounding measurement of telomere length (Shiels, 2010;Aviv et al., 2011). The cyclin-dependent kinase inhibitor (CDKN)2A hasbeen validated as an alternative BoA, which may represent a morereproducible measure of biological age (Shiels, 2010). Elevated CDKN2Atranscription occurs with increasing age in both peripheral bloodleucocytes (Liu et al., 2009) and solid organs, where it correlates withorgan function (Koppelstaetter et al., 2008). In this study, we investi-gated the correlation between C-HC and BoAs including telomere length,CDKN2A and the related transcripts CDKN2B and ARF. We hypothesizethat viral persistence induces non-cell-autonomous senescence, whichmay accelerate development of age-related diseases.Study participants were recruited into two groups: healthy controls(n = 24) who were negative for HCV-specific antibodies and patientswith C-HC (n = 43) who were positive for both HCV-specific antibodiesand viral RNA (Table S1). No significant differences were observed ingender, ethnicity, age or body mass index of healthy controls andpatients with C-HC. Alanine transaminase values were significantlyhigher in the C-HC group compared with controls consistent with thepresence of liver disease.Higher expression of CDKN2A (P = 0.0002), ARF (P = 0.0008) andCDKN2B (P = 0.0002) was observed in peripheral blood mononuclearcells (PBMCs) of patients with C-HC, compared with healthy controls(Fig. 1A and B, and Table S1). Elevated expression of CDKN2Atranscripts coincided with increased p16 protein levels in PBMCs frompatients with C-HC (Fig.S1). By contrast, no statistical difference wasfound in relative telomere length (P = 0.2176, Fig. 1C). To investigatewhether these biomarkers were altered due to disease state or viralgenotype, the C-HC group was divided according to the presence orabsence of liver cirrhosis (measured by transient elastography) and viralgenotype (either genotype 1 or genotype 3). In patients with livercirrhosis (n = 14), expression of CDKN2A and ARF was significantlyhigher compared with those without liver cirrhosis (n = 27) (Fig. 2A).CDKN2B expression and p16 protein levels showed the same trendalthough they failed to reach statistical significance (Fig. 2A andFig. S1C). No significant differences were noted in relative telomereCorrespondenceJohn McLauchlan, MRC-University of Glasgow Centre for Virus Research, 8 ChurchStreet, Glasgow G11 5JR, Tel.: +0141 330 4028; fax: +0141 330 4029;e-mail: john.mclauchlan@glasgow.ac.ukPaul Gerard Shiels, University of Glasgow College of Medical, Veterinary & LifeSciences, Institute of Cancer Sciences, McGregor Building, Level 2 WesternInfirmary Glasgow, G11 6NT, Glasgow. Tel./fax: +0141 211 2138;e-mail: Paul.Shiels@glasgow.ac.uk*Shared first authors.†Shared last authors.This research was supported by funding from the UK Medical Research Council(MRC).Accepted for publication 16 June 2013ª 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use,distribution and reproduction in any medium, provided the original work is properly cited.1141Aging Cell (2013) 12, pp1141–1143 Doi: 10.1111/acel.12125Aging Celllength between C-HC patients with or without liver cirrhosis (Fig. 2B).Separating the patients with C-HC according to viral genotype (geno-type 1 (n = 23) and genotype 3 (n = 18)) showed no difference intelomere length or expression of CDKN2 locus transcripts (Supplemen-tary Fig. 2).Elevated transcription of CDKN2A, ARF and CDKN2B in PBMC isconsistent with C-HC-associated non-cell-autonomous senescence,resulting in increased biological aging in infected patients. This findingsupports reports linking accelerated aging and HCV (Kitay-Cohen et al.,2008; Hoare et al., 2010b) and implies that C-HC indirectly drives thedevelopment of senescence in PBMCs. While a trend towards decreasingtelomere length in C-HC patients with cirrhosis was seen, unlike previousfindings, HCV infection was not associated with a significant decrease intelomere length (Kitay-Cohen et al., 2008; Hoare et al., 2010b). Thisdifference is likely due to the use of different techniques and highlightsthe issues surrounding the use of any single measure as a definitive BoA(Shiels, 2010; Aviv et al., 2011).Our findings indicate that increased CDKN2 locus transcription inPBMCs is a surrogate marker for the degree of liver damage, with thehighest expression levels of these BoAs noted in C-HC patients withcirrhosis. Whether this is due solely to the progression of HCV infection oralternatively whether liver cirrhosis independently induces senescence isunknown. Elevated liver fibrosis and cirrhosis have been reported in micewhere the p53-dependent senescence programme had been ablated(Lujambio et al., 2013). In this study, the inductionof p53-dependent non-cell-autonomous senescence acts tomaintain organ integrity and suppressliver damage; our findings are consistent with this model and providebiomarkers for exploring this in in vivo human studies.The observation of altered CDKN2 locus transcription, in associationwith HCV infection, is consistent with non-cell-autonomous senescence.Our study provides biomarkers for addressing the role of senescence inC-HC infection and may aid patient management as prognostic tools forthe progression of liver disease and the development of extrahepaticcomplications.CDKN2BCDKN2AARF−2 0Log FoldChange2C CCCCC CC C CH C C CCCCC C C CCCH H H HHHH H H H H H H H H H H H H H HHHH H H H HHHH H H H HHHH H H(A)Healthy controls C-HC patientsFold changeARF CDKN2A CDKN2B02468*** *** ***(B)Telomere length (T/S)0.00.51.01.5(C)4Fig. 1 Expression of CDKN2 locustranscripts and relative telomere length inpatients with C-HC and healthy controls.Heat map (A) and expression profile (B) ofCDKN2 locus transcripts from patients withC-HC (H; n = 41) and healthy controls (C;n = 22). (C) Relative telomere length inwhole blood from patients with C-HC(n = 42) compared with healthy controls(n = 24). Data are presented as mean with95% confidence intervals; ***denotesP < 0.001.Healthy controls C-HC without cirrhosis C-HC with cirrhosisFold changeARF CDKN2A CDKN2B04812************(A) (B)Telomere length (T/S)0.00.51.01.5Fig. 2 Expression of CDKN2 locustranscripts and relative telomere length inC-HC patients with/without liver cirrhosisand healthy controls. (A) Expression ofCDKN2 locus transcripts from C-HCpatients with (n = 14) or without (n = 27)liver cirrhosis compared with healthycontrols. (B) Relative telomere length inwhole blood from C-HC patients with(n = 15) or without (n = 27) liver cirrhosiscompared with healthy controls. Data arepresented as mean with 95% confidenceintervals; *P < 0.05, ***P < 0.001.Accelerated aging during chronic hepatitis C infection, M. W. Robinson et al.1142ª 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.Author contributionsMWR and DM were involved in study design, data analysis and draftingof manuscript; RS, SB and PRM were involved in patient recruitment;AHP, JM and PGS were involved in study design and critical review of themanuscript.DisclosuresAll authors declare no conflict of interests.ReferencesAviv A, Hunt SC, Lin J, Cao X, Kimura M, Blackburn E (2011) Impartial comparativeanalysis of measurement of leukocyte telomere length/DNA content by Southernblots and qPCR. Nucleic Acids Res. 39, e134.Deeks SG (2011) HIV infection, inflammation, immunosenescence, and aging.Annu. Rev. Med. 62, 141–155.Grebely J, Dore GJ (2011) What is killing people with hepatitis C virus infection?Semin. Liver Dis. 31, 331–339.Hoare M, Das T, Alexander G (2010a) Ageing, telomeres, senescence, and liverinjury. J. Hepatol. 53, 950–961.Hoare M, Gelson WT, Das A, Fletcher JM, Davies SE, Curran MD, Vowler SL, MainiMK, Akbar AN, Alexander GJ (2010b) CD4 + T-lymphocyte telomere length isrelated to fibrosis stage, clinical outcome and treatment response in chronichepatitis C virus infection. J. Hepatol. 53, 252–260.Kitay-Cohen Y, Goldberg-Bittman L, Hadary R, Fejgin MD, Amiel A (2008)Telomere length in Hepatitis C. Cancer Genet. Cytogenet. 187, 34–38.Koppelstaetter C, Schratzberger G, Perco P, Hofer J, Mark W, Ollinger R,Oberbauer R, Schwarz C, Mitterbauer C, Kainz A, Karkoszka H, Wiecek A,Mayer B, Mayer G (2008) Markers of cellular senescence in zero hour biopsiespredict outcome in renal transplantation. Aging Cell 7, 491–497.Lee MH, Yang HI, Lu SN, Jen CL, You SL, Wang LY, Wang CH, Chen WJ, Chen CJ(2012) Chronic hepatitis C virus infection increases mortality from hepatic andextrahepatic diseases: a community-based long-term prospective study. J. Infect.Dis. 206, 469–477.Liu Y, Sanoff HK, Cho H, Burd CE, Torrice C, Ibrahim JG, Thomas NE, Sharpless NE(2009) Expression of p16(INK4a) in peripheral blood T-cells is a biomarker ofhuman aging. Aging Cell 8, 439–448.Lujambio A, Akkari L, Simon J, Grace D, Tschaharganeh DF, Bolden JE, Zhao Z,Thapar V, Joyce JA, Krizhanovsky V, Lowe SW (2013) Non-Cell-AutonomousTumor Suppression by p53. Cell 153, 449–460.Seeff LB (2009) The history of the “natural history” of hepatitis C (1968-2009).Liver Int. 29(Suppl 1), 89–99.Sekoguchi S, Nakajima T, Moriguchi M, Jo M, Nishikawa T, Katagishi T, Kimura H,Minami M, Itoh Y, Kagawa K, Tani Y, Okanoue T (2007) Role of cell-cycleturnover and oxidative stress in telomere shortening and cellular senescence inpatients with chronic hepatitis C. J. Gastroenterol. Hepatol. 22, 182–190.Shiels PG (2010) Improving precision in investigating aging: why telomeres cancause problems. J. Gerontol. A Biol. Sci. Med. Sci. 65, 789–791.Supporting InformationAdditional Supporting Information may be found in the online version of thisarticle at the publisher’s web-site.Data S1. Materials and Methods.Fig. S1. CDKN2A/p16 protein expression in PBMC protein extracts.Fig. S2. CDKN2 locus transcript expression with samples grouped by HCVgenotype.Table S1. Participants clinical characteristics.Accelerated aging during chronic hepatitis C infection, M. W. Robinson et al. 1143ª 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

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Non cell autonomous upregulation of CDKN2 transcription linked to progression of chronic hepatitis C disease

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