Human telomerase disease mutants and its relation with hepatocarcinoma

Abstract

Telomerase is a special reverse transcriptase, which adds telomeric DNA repeats to the ends of chromosome to offset loss. A vast majority of cancer cells have been shown that their telomerase was up-regulated and sustain proliferation and growth. Hepatocellular carcinoma (HCC) is one of the most commonly occurring cancers worldwide. It is also one of the leading causes of cancer death, and is connected with abnormal telomerase function. However, reports about the telomerase mutations and HCC are still insufficient. In this review, the structure and mechanism of action of telomerase, inherited disorders caused by its mutations, hepatocarcinoma, and drug development targeting telomerase are reviewed. However, further investigations are needed to elucidate human telomerase RNA gene regulation for initiation and progression of the liver cancer.

Keywords

Telomerase / mutants / hepatocarcinoma / target

References

[1] de Lange T.Protection of mammalian telomeres..Oncogene2002;21:532-40

[2] de Lange T.How telomeres solve the end-protection problem..Science2009;326:948-52 PMCID:PMC2819049

[3] Lingner J,Cech TR.Telomerase and DNA end replication - no longer a lagging-strand problem?.Science1995;269:1533-4

[4] Kim NW,Prowse KR,West MD,Coviello GM,Weinrich SL.Specific association of human telomerase activity with immortal cells and cancer..Science1994;266:2011-5

[5] Fogarty PF,Wiestner A,Sloand E,Read EJ,Young NS.Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA..Lancet2003;362:1628-30

[6] Armanios MY,Cogan JD,Ingersoll RG,Lawson WE,Vulto I,Lansdorp PM,Loyd JE.Telomerase mutations in families with idiopathic pulmonary fibrosis..N Engl J Med2007;356:1317-26

[7] Vulliamy TJ,Knight SW,Mason PJ.Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation..Blood2006;107:2680-5

[8] Tsukuma H,Ajiki W.Liver cancer and its prevention..Asian Pac J Cancer Prev2005;6:244-50

[9] Ding D,Hua D,Li L,Gao F,Ren G,Lin B.Recurrent targeted genes of hepatitis B virus in the liver cancer genomes identified by a next-generation sequencing-based approach..PLoS Genet2012;8:e1003065 PMCID:PMC3516541

[10] Collins K.Telomerase in the human organism..Oncogene2002;21:564-79

[11] Hanahan D.The hallmarks of cancer..Cell2000;100:57-70

[12] Carulli L.Telomere and telomerase in chronic liver disease and hepatocarcinoma..World J Gastroenterol2014;20:6287-92 PMCID:PMC4033466

[13] Satyanarayana A,Rudolph KL.Telomeres and telomerase: a dual role in hepatocarcinogenesis..Hepatology2004;40:276-83

[14] Quaas A,Tharun L,Krech T,Grob TJ.Frequency of TERT promoter mutations in primary tumors of the liver..Virchows Arch2014;465:673-7

[15] Fujimoto A,Abe T,Hosoda F,Aoki M,Kubo M,Arai Y,Shirakihara T,Shibuya T,Watanabe-Makino K,Nakamura H,Ojima H,Okusaka T,Shigekawa Y,Arihiro K,Gotoh K,Ariizumi S,Yamada T,Kosuge T,Kamatani N,Nakagama H,Tsunoda T,Nakagawa H.Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators..Nat Genet2012;44:760-4

[16] Hartmann D,Thaler M,N'kontchou G,Bauer K,Kloos N,Song Z,Kleger A,Strnad P,Günes C,Deterding K,Ju Z,Xiao F,Schrezenmeier H,Ziol M,Jarek M,Beaugrand M.Telomerase gene mutations are associated with cirrhosis formation..Hepatology2011;53:1608-17

[17] Buseman CM., Wright WE, Shay JW. Is telomerase a viable target in cancer?.Mutat Res2012;730:90-7 PMCID:PMC3375693

[18] Shippen-Lentz D.Functional evidence for an rna template in telomerase..Science1990;247:546-52

[19] Weinrich SL,Ma L,Tesmer VM,Bodnar AG,Kim NW,Taylor RD,Andrews WH,Shay JW,Morin GB.Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT..Nat Genet1997;17:498-502

[20] Nakamura TM,Chapman KB,Andrews WH,Harley CB.Telomerase catalytic subunit homologs from fission yeast and human..Science1997;277:955-9

[21] Yu RM,Kong RY,Mok HO.Hypoxia induces telomerase reverse transcriptase (TERT) gene expression in non-tumor fish tissues in vivo: the marine medaka (Oryzias melastigma) model..BMC Mol Biol2006;7:27 PMCID:PMC1578579

[22] Gillis AJ,Skordalakes E.Structure of the tribolium castaneum telomerase catalytic subunit TERT..Nature2008;455:633-47

[23] Huang J,Wu J,Bley CJ,Wu LJ,Chen JJ.Structural basis for protein-RNA recognition in telomerase..Nat Struct Mol Biol2014;21:507-12 PMCID:PMC4409868

[24] Qi X,Brown AF,Podlevsky JD.RNA/DNA hybrid binding affinity determines telomerase template-translocation efficiency..EMBO J2012;31:150-61 PMCID:PMC3252576

[25] Parks JW.Coordinated DNA dynamics during the human telomerase catalytic cycle..Nat Commun2014;5:4146 PMCID:PMC4107311

[26] Theimer CA,Chim N,Breece KE,Feigon J.Structural and functional characterization of human telomerase RNA processing and cajal body localization signals..Mol Cell2007;27:869-81

[27] Cristofari G,Reichenbach P,Terns RM,Lingner J.Human telomerase RNA accumulation in Cajal bodies facilitates telomerase recruitment to telomeres and telomere elongation..Mol Cell2007;27:882-9

[28] Robart AR.Investigation of human telomerase holoenzyme assembly, activity, and processivity using disease-linked subunit variants..J Biol Chem2010;285:4375-86 PMCID:PMC2836042

[29] Podlevsky JD,Omana RV,Chen JJ.The telomerase database..Nucleic Acids Res2008;36:D339-43 PMCID:PMC2238860

[30] Alder JK,Brown AF,Lawson WE,Phillips JA3rd,Chen JJ.Ancestral mutation in telomerase causes defects in repeat addition processivity and manifests as familial pulmonary fibrosis..PLoS Genet2011;7:e1001352 PMCID:PMC3069110

[31] Armanios M.Telomerase and idiopathic pulmonary fibrosis..Mutat Res2012;730:52-8 PMCID:PMC3292861

[32] Nishio N.Recent progress in dyskeratosis congenita..Int J Hematol2010;92:419-24

[33] Vulliamy T,Dokal I.Association between aplastic anaemia and mutations in telomerase RNA..Lancet2002;359:2168-70

[34] Hoare M,Alexander G.Ageing, telomeres, senescence, and liver injury..J Hepatol2010;53:950-61

[35] Podlevsky JD.It all comes together at the ends: telomerase structure, function, and biogenesis..Mutat Res2012;730:3-11 PMCID:PMC4420735

[36] Carulli L.Telomere shortening as genetic risk factor of liver cirrhosis..World J Gastroenterol2015;21:379-83 PMCID:PMC4292269

[37] Wiemann SU,Tsahuridu M,Zender L,Flemming P,Blasco MA,Rudolph KL.Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis..FASEB J2002;16:935-42

[38] Kitada T,Kawakita N,Monna T.Telomere shortening in chronic liver-diseases..Biochem Biophys Res Commun1995;211:33-9

[39] Liu B,Huang C.Dyskerin overexpression in human hepatocellular carcinoma is associated with advanced clinical stage and poor patient prognosis..PLoS One2012;7:e43147 PMCID:PMC3418259

[40] Mizuno H,Shirasaki T,Yamashita T,Kaneko S.Heterogeneous nuclear ribonucleoprotein A2/B1 in association with hTERT is a potential biomarker for hepatocellular carcinoma..Liver Int2012;32:1146-55

[41] Lechel A,Begus Y,Kamino K,Kubicka S,Jonkers J.Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease..Gastroenterology2007;132:1465-75

[42] Farazi PA,Jiang S,Rudolph KL.Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma..Cancer Res2003;63:5021-7

[43] Huang DS,He XJ,Yang R,Meng Q,Wang W,Xu L,Zhao ZS,Wang HJ,Xia YJ,Zhang RX,Zhao ZK,Yu S,Liang J,Jiao Y,Tao HQ.Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation..Eur J Cancer2015;51:969-76 PMCID:PMC4467782

[44] Quaas A,Tharun L,Krech T,Grob TJ.Frequency of TERT promoter mutations in primary tumors of the liver..Virchows Arch2014;465:673-7

[45] Nagao K,Endo H,Hikiji K.Telomerase reverse transcriptase mRNA expression and telomerase activity in hepatocellular carcinoma..J Gastroenterol1999;34:83-7

[46] Shimojima M,Hisatomi H,Moriyama M.(2004) Detection of telomerase activity, telomerase RNA component, and telomerase reverse transcriptase in human hepatocellular carcinoma..Hepatol Res2004;29:31-8

[47] Cevik D,Ozturk M.Common telomerase reverse transcriptase promoter mutations in hepatocellular carcinomas from different geographical locations..World J Gastroenterol2015;21:311-7 PMCID:PMC4284350

[48] Valenti L,Maggioni M,Rametta R,Fargion S,Fracanzani AL.Liver transplantation for hepatocellular carcinoma in a patient with a novel telomerase mutation and steatosis..J Hepatol2013;58:399-401

[49] Dikmen ZG,Jackson S,Tressler R,Wright WE.In vivo inhibition of lung cancer by GRN163L: a novel human telomerase inhibitor..Cancer Res2005;65:7866-73

[50] Burchett KM,Ouellette MM.Telomerase inhibitor Imetelstat (GRN163L) limits the lifespan of human pancreatic cancer cells..PloS One2014;9:e85155 PMCID:PMC3883701

[51] Molckovsky A.First-in-class, first-in-human phase I results of targeted agents: highlights of the 2008 American society of clinical oncology meeting..J Hematol Oncol2008;1:20 PMCID:PMC2647552

[52] Parsch D,Brümmendorf TH.Consequences of telomerase inhibition by BIBR1532 on proliferation and chemosensitivity of chondrosarcoma cell lines..Cancer Invest2008;26:590-6

[53] Bryan C,Hoffman H,Sweeney M.Structural basis of telomerase inhibition by the highly specific BIBR1532..Structure2015;23:1934-42 PMCID:PMC4598299

[54] Kellermann G,Dingli F,Naud-Martin D,Loew D,Teulade-Fichou MP.Identification of human telomerase assembly inhibitors enabled by a novel method to produce hTERT..Nucleic Acids Res2015;43:e99 PMCID:PMC4551907

[55] Chen ZF,Qin JL,Li YL,Liu YC.Water-soluble ruthenium(II) complexes with chiral 4-(2,3-dihydroxypropyl)-formamide oxoaporphine (FOA): in vitro and in vivo anticancer activity by stabilization of G-quadruplex DNA, inhibition of telomerase activity, and induction of tumor cell apoptosis..J Med Chem2015;58:4771-89

[56] Wei C,Gao N.Interactions of terpyridines and their Pt(II) complexes with G-quadruplex DNAs and telomerase inhibition..Int J Biol Macromol2013;57:1-8

[57] Staff C,Frodin JE,Liljefors M.Telomerase (GV1001) vaccination together with gemcitabine in advanced pancreatic cancer patients..Int J Oncol2014;45:1293-303

[58] Kotsakis A,Vetsika EK,Dermitzaki EK,Kentepozidis N,Georgoulias V.A phase II trial evaluating the clinical and immunologic response of HLA-A2(+) non-small cell lung cancer patients vaccinated with an hTERT cryptic peptide..Lung Cancer2014;86:59-66

[59] Mizukoshi E,Kitahara M,Arai K,Fushimi K,Kishi H,Kaneko S.Immunological features of T cells induced by human telomerase reverse transcriptase-derived peptides in patients with hepatocellular carcinoma..Cancer Lett2015;364:98-105

[60] Xi LH.Inventory of telomerase components in human cells reveals multiple subpopulations of hTR and hTERT..Nucleic Acids Res2014;42:8565-77 PMCID:PMC4117779