Inhibition of hepatocellular carcinoma growth by adenovirus‑mediated expression of human telomerase reverse transcriptase COOH-27 terminal polypeptide in mice

He,Lei; Gong,Han-Xian; Li,Xiang-Pen; Wang,Yi-Dong; Li,Yi; Huang,Jun-Jian; Xie,Dan; Kung,Hsiang-Fu; Peng,Ying

doi:10.3892/ol.2013.1470

Inhibition of hepatocellular carcinoma growth by adenovirus‑mediated expression of human telomerase reverse transcriptase COOH-27 terminal polypeptide in mice

Authors:
- Lei He
- Han-Xian Gong
- Xiang-Pen Li
- Yi-Dong Wang
- Yi Li
- Jun-Jian Huang
- Dan Xie
- Hsiang-Fu Kung
- Ying Peng
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Affiliations: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China, Laboratory of Tumor and Molecular Biology, Beijing Institute of Biotechnology, Beijing 100071, P.R. China, State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China, Stanley Ho Center for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, P.R. China
Published online on: July 16, 2013 https://doi.org/10.3892/ol.2013.1470
Pages: 748-752

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Abstract

A 27‑kDa C‑terminal fragment of human telomerase reverse transcriptase, hTERTC27, has previously been reported to inhibit the growth and tumorigenicity of HeLa human cervical cancer cells and U87‑MG human glioblastoma multiforme cells. However, the antitumor effects of hTERTC27 in hepatoma and its underlying mechanisms are unclear. In the current study, the therapeutic effect of hTERTC27, mediated by recombinant adenovirus, in hepatocellular carcinoma (HCC) was explored in vitro and in vivo to investigate the possible mechanisms. The results indicated that recombinant adenovirus carrying hTERTC27 (rAdv‑hTERTC27) effectively inhibited the growth and induced apoptosis of the Hepa 1‑6 HCC cells. Dendritic cells transduced with rAdv‑hTERTC27 were highly effective at inducing antigen‑specific T cell proliferation and increasing the activated cytotoxicity of T cells against Hepa 1‑6 cells. HCC was inhibited significantly when a single dose of 5x107 pfu rAdv‑hTERTC27 was administered intravenously. In summary, the results of this study demonstrated that rAdv‑hTERTC27 may serve as a reagent for intravenous administration when combined with telomerase‑based gene therapy and immunotherapy for cancer.

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1	Fung SK and Lok AS: Management of patients with hepatitis B virus-induced cirrhosis. J Hepatol. 42(Suppl 1): S54–S64. 2005. View Article : Google Scholar : PubMed/NCBI
2	Huang YH, Wu JC, Chen SC, Chen CH, Chiang JH, Huo TI, Lee PC, Chang FY and Lee SD: Survival benefit of transcatheter arterial chemoembolization in patients with hepatocellular carcinoma larger than 10 cm in diameter. Aliment Pharmacol Ther. 23:129–135. 2006. View Article : Google Scholar : PubMed/NCBI
3	Rampone B, Schiavone B, Martino A, Viviano C and Confuorto G: Current management strategy of hepatocellular carcinoma. World J Gastroenterol. 15:3210–3216. 2009. View Article : Google Scholar : PubMed/NCBI
4	Ng KK and Poon RT: Current treatment strategy for hepatocellular carcinoma. Saudi Med J. 28:1330–1338. 2007.PubMed/NCBI
5	Makower D, Rozenblit A, Kaufman H, Edelman M, Lane ME, Zwiebel J, Haynes H and Wadler S: Phase II clinical trial of intralesional administration of the oncolytic adenovirus ONYX-015 in patients with hepatobiliary tumors with correlative p53 studies. Clin Cancer Res. 9:693–702. 2003.PubMed/NCBI
6	Reid T, Galanis E, Abbruzzese J, Sze D, Wein LM, Andrews J, Randlev B, Heise C, Uprichard M, Hatfield M, et al: Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints. Cancer Res. 62:6070–6079. 2002.PubMed/NCBI
7	Abdul-Ghani R, Ohana P, Matouk I, Ayesh S, Ayesh B, Laster M, Bibi O, Giladi H, Molnar-Kimber K, Sughayer MA, et al: Use of transcriptional regulatory sequences of telomerase (hTER and hTERT) for selective killing of cancer cells. Mol Ther. 2:539–544. 2000. View Article : Google Scholar : PubMed/NCBI
8	Mizukoshi E, Nakamoto Y, Marukawa Y, Arai K, Yamashita T, Tsuji H, Kuzushima K, Takiguchi M and Kaneko S: Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma. Hepatology. 43:1284–1294. 2006. View Article : Google Scholar : PubMed/NCBI
9	Zou W, Luo C, Zhang Z, Liu J, Gu J, Pei Z, Qian C and Liu X: A novel oncolytic adenovirus targeting to telomerase activity in tumor cells with potent. Oncogene. 23:457–464. 2004. View Article : Google Scholar : PubMed/NCBI
10	Huang JJ, Lin MC, Bai YX, Jing DD, Wong BC, Han SW, Lin J, Xu B, Huang CF and Kung HF: Ectopic expression of a COOH-terminal fragment of the human telomerase reverse transcriptase leads to telomere dysfunction and reduction of growth and tumorigenicity in HeLa cells. Cancer Res. 62:3226–3232. 2002.PubMed/NCBI
11	Shay JW, Zou Y, Hiyama E and Wright WE: Telomerase and cancer. Hum Mol Genet. 10:677–685. 2001. View Article : Google Scholar
12	Huo LF, Tang JW, Huang JJ, Huang PT, Huang CF, Kung HF and Lin MC: Cancer immunotherapy targeting the telomerase reverse transcriptase. Cell Mol Immunol. 3:1–11. 2006.PubMed/NCBI
13	Ng SS, Gao Y, Chau DH, Li GH, Lai LH, Huang PT, Huang CF, Huang JJ, Chen YC, Kung HF and Lin MC: A novel glioblastoma cancer gene therapy using AAV-mediated long-term expression of human TERT C-terminal polypeptide. Cancer Gene Ther. 14:561–572. 2007. View Article : Google Scholar : PubMed/NCBI
14	Gong HX, He L, Li XP, Wang YD, Li Y, Huang JJ, Wang Z, Xie D, Kung HF and Peng Y: Effective antitumor immunity against murine gliomas using dendritic cells transduced with hTERTC27 recombinant adenovirus. Oncol Rep. 27:1163–1169. 2012.PubMed/NCBI
15	Yin D, Woodruff M, Zhang Y, Whaley S, Miao J, Ferslew K, Zhao J and Stuart C: Morphine promotes Jurkat cell apoptosis through pro-apoptotic FADD/P53 and anti-apoptotic PI3K/Akt/NF-kappaB pathways. J Neuroimmunol. 174:101–107. 2006. View Article : Google Scholar : PubMed/NCBI
16	Cowell JK and Franks LM: A rapid method for accurate DNA measurements in single cells in situ using a simple microfluorimeter and Hoechst 33258 as a quantitative fluorochrome. J Histochem Cytochem. 28:206–210. 1980. View Article : Google Scholar : PubMed/NCBI
17	Osada S, Ebihara I, Setoguchi Y, Takahashi H, Tomino Y and Koide H: Gene therapy for renal anemia in mice with ploycystic kidney using an adenovirus vector encoding the human erythropoietin gene. Kidney Int. 55:1234–1240. 1999. View Article : Google Scholar : PubMed/NCBI
18	Mohr A, Lyons M, Deedigan L, Harte T, Shaw G, Howard L, Barry F, O’Brien T and Zwacka R: Mesenchymal stem cells expressing TRAIL lead to tumour growth inhibition in an experimental lung cancer model. J Cell Mol Med. 12:2628–2643. 2008. View Article : Google Scholar : PubMed/NCBI
19	Reid T, Warren R and Kirn D: Intravascular adenoviral agents in cancer patients: lessons from clinical trial. Cancer Gene Ther. 9:979–986. 2002. View Article : Google Scholar : PubMed/NCBI
20	Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL and Shay JW: Specific association of human telomerase activity with immortal cells and cancer. Science. 266:2011–2015. 1994. View Article : Google Scholar : PubMed/NCBI
21	Liao ZL, Luo G, Xie X, Tang XD, Bai JY, Guo H and Yang SM: Diepitope multiple antigen peptide of hTERT trigger stronger anti-tumor immune responses in vitro. Int Immunopharmacol. 16:444–450. 2013. View Article : Google Scholar : PubMed/NCBI
22	Hashimoto Y, Tazawa H, Teraishi F, Kojima T, Watanabe Y, Uno F, Yano S, Urata Y, Kagawa S and Fujiwara T: The hTERT promoter enhances the antitumor activity of an oncolytic adenovirus under a hypoxic microenvironment. PLoS One. 7:e392922012. View Article : Google Scholar
23	Iezzi G, Boni A, Degl’Innocenti E, Grioni M, Bertilaccio MT and Bellone M: Type 2 cytotoxic T lymphocytes modulate the activity of dendritic cells toward type 2 immune responses. J Immunol. 177:2131–2137. 2006. View Article : Google Scholar
24	Knutson KL and Disis ML: Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother. 54:721–728. 2005. View Article : Google Scholar : PubMed/NCBI
25	Pipkin ME, Sacks JA, Cruz-Guilloty F, Lichtenheld MG, Bevan MJ and Rao A: Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity. 32:79–90. 2010. View Article : Google Scholar : PubMed/NCBI
26	Nishihori Y, Kato K, Tanaka M, Okamoto T, Hagiwara S, Araki N, Kogawa K, Kuribayashi K, Nakamura K and Niitsu Y: Interleukin-2 gene transfer potentiates the alpha-galactosylceramide-stimulated antitumor effect by the induction of TRAIL in NKT and NK cells in mouse models of subcutaneous and metastatic carcinoma. Cancer Biol Ther. 8:1763–1770. 2009. View Article : Google Scholar
27	Koido S, Homma S, Hara E, et al: In vitro generation of cytotoxic and regulatory T cells by fusions of human dendritic cells and hepatocellular carcinoma cells. J Transl Med. 6:512008. View Article : Google Scholar : PubMed/NCBI
28	Oh ST, Kim CH, Park MY, Won EH, Sohn HJ, Cho HI, Kang WK, Hong YK and Kim TG: Dendritic cells transduced with recombinant adenoviruses induce more efficient anti-tumor immunity than dendritic cells pulsed with peptide. Vaccine. 24:2860–2868. 2006. View Article : Google Scholar : PubMed/NCBI
29	Chen L, Tang XD, Yu ST, Ai ZH, Fang DC, Cai YG, Luo YH, Liang GP and Yang SM: Induction of anti-tumour immunity by dendritic cells transduced with hTERT recombinant adenovirus in mice. J Pathol. 217:685–692. 2009. View Article : Google Scholar : PubMed/NCBI
30	Darlington GJ, Bernhard HP, Miller RA and Ruddle FH: Expression of liver phenotypes in cultured mouse hepatoma cells. J Natl Cancer Inst. 64:809–819. 1980.PubMed/NCBI
31	Gao Y, Ng SS, Chau DH, Yao H, Yang C, Man K, Huang PT, Huang C, Huang JJ, Kung HF and Lin MC: Development of recombinant adeno-associated virus and adenovirus cocktail system for efficient hTERTC27 polypeptide-mediated cancer gene therapy. Cancer Gene Ther. 15:723–732. 2008. View Article : Google Scholar : PubMed/NCBI