Page 121 - Read Online
P. 121

target for screening small molecules capable to interfere with   4.   Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL,
           telomerase assembly. Indeed, for macromolecular complex,   Coviello GM, Wright WE, Weinrich SL, Shay JW. Specific association
           the interfacial drugs have a remarkable potential application.  of  human  telomerase  activity  with  immortal  cells  and  cancer.  Science
                                                                 1994;266:2011-5.
                                                              5.   Fogarty PF, Yamaguchi H, Wiestner A, Baerlocher GM, Sloand E, Zeng
           G-quadruplex stabilizers are potent ligands that indirectly   WS, Read EJ, Lansdorp PM, Young NS. Late presentation of dyskeratosis
           target  telomerase  resulting  in  inhibition  of  its  activity.   congenita as apparently acquired aplastic anaemia due to mutations in
           BRACO-19, RHPS4 and Telomestatin are commonly         telomerase RNA. Lancet 2003;362:1628-30.
           studied G-quadruplex binding ligands. Recently there are   6.   Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C,
                                                                 Lawson WE, Xie MY, Vulto I, Phillips JA 3rd, Lansdorp PM, Greider CW,
           several studies showed anticancer drug candidates with   Loyd JE. Telomerase mutations in families with idiopathic pulmonary
           G-guadruplex as targets. [55,56]                      fibrosis. N Engl J Med 2007;356:1317-26.
                                                              7.   Vulliamy  TJ, Marrone A, Knight SW,  Walne A, Mason PJ, Dokal I.
           Immunotherapy approach which induces T lymphocytes to   Mutations in dyskeratosis congenita: their impact on telomere length and
           respond to hTERT antigens in malignant tumor has shown   the diversity of clinical presentation. Blood 2006;107:2680-5.
           good  inhibitory  effect.  Preclinical  studies  with  hTERT   8.   Tsukuma H, Tanaka H, Ajiki W, Oshima A. Liver cancer and its prevention.
                                                                 Asian Pac J Cancer Prev 2005;6:244-50.
           peptides have led to successful progress in the telomerase-  9.   Ding D, Lou X, Hua D, Yu W, Li L, Wang J, Gao F, Zhao N, Ren G, Li
           targeting immunotherapies. Some telomerase vaccination   L, Lin B. Recurrent targeted genes of hepatitis B virus in the liver cancer
           such as Vx-001, GV1001 showed promising clinical outcome   genomes  identified  by  a  next-generation  sequencing-based  approach.
           for different types of tumor. [57,58]  Recently an hTERT-derived   PLoS Genet 2012;8:e1003065.
           peptide [hTERT(461)] have shown clinical benefits in HCC   10.  Collins K, Mitchell JR. Telomerase in the human organism. Oncogene
                                                                 2002;21:564-79.
           patients. [59]                                     11.  Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70.
                                                              12.  Carulli L, Anzivino C. Telomere and telomerase in chronic liver disease
           CONCLUSION AND PERSPECTIVE                            and hepatocarcinoma. World J Gastroenterol 2014;20:6287-92.
                                                              13.  Satyanarayana A, Manns MP, Rudolph KL. Telomeres and telomerase: a
                                                                 dual role in hepatocarcinogenesis. Hepatology 2004;40:276-83.
           Telomere shortening plays an important role in cell   14.  Quaas A, Oldopp T, Tharun L, Klingenfeld C, Krech T, Sauter G, Grob
           senescence.  Telomerase  which  maintains  the  length  of   TJ. Frequency of TERT promoter mutations in primary tumors of the liver.
           telomere connects with aging, chronic diseases as well as   Virchows Arch 2014;465:673-7.
           cancer promotion and progression. [17,34]  By looking into   15.  Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH,
           the telomerase gene mutations, the relation between the   Aoki M, Hosono N, Kubo M, Miya F, Arai Y, Takahashi H, Shirakihara
           mutants and liver disease including HCC probably is due to   T, Nagasaki M,  Shibuya  T, Nakano K,  Watanabe-Makino K,  Tanaka
                                                                 H, Nakamura H, Kusuda J, Ojima H, Shimada K, Okusaka T, Ueno M,
           the reduced activity. Meanwhile, the mutations at noncoding   Shigekawa Y, Kawakami Y, Arihiro K, Ohdan H, Gotoh K, Ishikawa O,
           sequence of the telomerase also involved in the development   Ariizumi S, Yamamoto M, Yamada T, Chayama K, Kosuge T, Yamaue H,
           of the HCC by regulating the expression level of active   Kamatani N, Miyano S, Nakagama H, Nakamura Y, Tsunoda T, Shibata
           enzyme. It is commonly believed that the expression of hTERT   T, Nakagawa H. Whole-genome sequencing of liver cancers identifies
           may be a definitive factor in the activation of telomerase in   etiological  influences  on  mutation  patterns  and  recurrent  mutations  in
                                                                 chromatin regulators. Nat Genet 2012;44:760-4.
           hepatocarcinogenesis,  however according to the recent   16.  Hartmann D, Srivastava U, Thaler M, Kleinhans KN, N’kontchou G,
                             [46]
           paper from Xi et al.  overexpression of either hTR or hTERT   Scheffold A, Bauer K, Kratzer RF, Kloos N, Katz SF, Song Z, Begus-
                          [60]
           could increase telomerase activity which indicates that the   Nahrmann Y, Kleger A, von Figura G, Strnad P, Lechel A, Günes C,
           two  core  components  assemble  into  active  telomerase  is   Potthoff A, Deterding K, Wedemeyer H, Ju Z, Song G, Xiao F, Gillen
           an equilibrium process. Further investigation is required   S, Schrezenmeier H, Mertens T, Ziol M, Friess H, Jarek M, Manns MP,
                                                                 Beaugrand M, Rudolph KL. Telomerase gene mutations are associated
           to elucidate the regulation of hTR gene with initiation and   with cirrhosis formation. Hepatology 2011;53:1608-17.
           progression of the liver cancer.                   17.  Buseman CM., Wright WE, Shay JW. Is telomerase a viable target in
                                                                 cancer? Mutat Res 2012;730:90-7.
           Financial support and sponsorship                  18.  Shippenlentz D, Blackburn EH. Functional evidence for an rna template in
           This work was supported by the National Natural Science   telomerase. Science 1990;247:546-52.
           Foundation of China (Grant no. 81370088) and the Supporting   19.  Weinrich SL, Pruzan R, Ma L, Ouellette M, Tesmer VM, Holt SE, Bodnar
                                                                 AG, Lichtsteiner S, Kim NW, Trager JB, Taylor RD, Carlos R, Andrews
           Plan of Education Ministry’s New Century Excellent Talents   WH, Wright WE, Shay JW, Harley CB, Morin GB. Reconstitution of
           (Grant no. NCET-13-0467).                             human  telomerase  with  the template  RNA  component  hTR  and  the
                                                                 catalytic protein subunit hTRT. Nat Genet 1997;17:498-502.
           Conflicts of interest                              20.  Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH,
           There are no conflicts of interest.                   Lingner J, Harley CB, Cech TR. Telomerase catalytic subunit homologs
                                                                 from fission yeast and human. Science 1997;277:955-9.
                                                              21.  Yu RM, Chen EX, Kong RY, Ng PK, Mok HO, Au DW. Hypoxia induces
           REFERENCES                                            telomerase reverse transcriptase (TERT) gene expression in non-tumor
                                                                 fish tissues in vivo: the marine medaka (Oryzias melastigma) model. BMC
           1.   de Lange T. Protection of mammalian telomeres. Oncogene 2002;21:532-  Mol Biol 2006;7:27.
               40.                                            22.  Gillis AJ, Schuller AP, Skordalakes E. Structure of the tribolium castaneum
           2.   de Lange T. How telomeres solve the end-protection problem. Science   telomerase catalytic subunit TERT. Nature 2008;455:633-47.
               2009;326:948-52.                               23.  Huang J, Brown AF, Wu J, Xue J, Bley CJ, Rand DP, Wu LJ, Zhang
           3.   Lingner J, Cooper JP, Cech TR. Telomerase and DNA end replication - no   RG, Chen JJ, Lei M. Structural basis for protein-RNA recognition in
               longer a lagging-strand problem? Science 1995;269:1533-4.  telomerase. Nat Struct Mol Biol 2014;21:507-12.

            112                                                            Hepatoma Research | Volume 2 | May 6, 2016
   116   117   118   119   120   121   122   123   124   125   126