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01-12-2012 | Original Research

Anticancer role of MUC1 aptamer–miR-29b chimera in epithelial ovarian carcinoma cells through regulation of PTEN methylation

Authors: Furong Dai, Yi Zhang, Xin Zhu, Nianchun Shan, Yuxiang Chen

Published in: Targeted Oncology | Issue 4/2012

Abstract

Ovarian cancer has a poor prognosis and advanced ovarian cancer lacks effective therapy. In this study, we seek to establish targeting therapy for ovarian cancer through tumor tissue-specific delivery of miRNA-29b to reexpress PTEN tumor-suppressor gene. A chimera (Chi-29b) was constructed to compose of a mucin 1 (MUC1) aptamer targeting tumor cell surface MUC1 protein and miR-29b inhibiting DNA methyltransferases’ expression, subsequently reexpressing PTEN gene. The specificity and efficacy of the chimera delivery were analyzed in OVCAR-3 ovarian tumor cells, and the biological activities of the chimera were identified by the expression of its downstream molecules and cell apoptosis. We demonstrated that Chi-29b chimera can be specifically delivered into OVCAR-3 cells in a concentration-dependent manner. Dicer efficiently cleaved the Chi-29b chimera to release miR-29b. Chi-29b chimera downregulated Dnmt1, Dnmt3a, and Dnmt3b protein levels; induced hypomethylation in PTEN promoter; and upregulated PTEN mRNA and protein expression in OVCAR-3 cells. Importantly, Chi-29b chimera significantly induced apoptosis in OVCAR-3 cells. Our study indicated that Chi-29b chimera can effectively exert antitumor effect through specific delivery of miR-29b into OVCAR-3 tumor cells, subsequently reexpressing PTEN gene and inducing cell apoptosis.

Van Simaeys D, López-Colón D, Sefah K, Sutphen R, Jimenez E, Tan W (2010) Study of the molecular recognition of aptamers selected through ovarian cancer cell-SELEX. PLoS One 5:e13770PubMedCrossRef

Hartge P (2010) Designing early detection programs for ovarian cancer. J Natl Cancer Inst 102:3–4PubMedCrossRef

Willmott LJ, Fruehauf JP (2010) Targeted therapy in ovarian cancer. J Oncol 2010:740472PubMedCrossRef

Morrison J, Haldar K, Kehoe S, Lawrie TA (2012) Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer. Cochrane Database Syst Rev 8:CD005343

Hess LM, Rong N, Monahan PO, Gupta P, Thomaskutty C, Matei D (2010) Continued chemotherapy after complete response to primary therapy among women with advanced ovarian cancer: a meta-analysis. Cancer 116:5251–5260PubMedCrossRef

Collinson FJ, Seligmann J, Perren TJ (2012) Ovarian cancer: advances in first-line treatment strategies with a particular focus on anti-angiogenic agents. Curr Oncol Rep. doi:10.1007/s11912-012-0274-4

Teoh D, Secord AA (2012) Antiangiogenic agents in combination with chemotherapy for the treatment of epithelial ovarian cancer. Int J Gynecol Cancer 22:348–359PubMedCrossRef

Lee RC, Ambros V (2001) An extensive class of small RNAs in Caenorhabditis elegans. Science 294:862–864PubMedCrossRef

Slack FJ, Weidhaas JB (2008) MicroRNA in cancer prognosis. N Engl J Med 359:2720–2722PubMedCrossRef

10.

Lou Y, Yang X, Wang F, Cui Z, Huang Y (2010) MicroRNA-21 promotes the cell proliferation, invasion and migration abilities in ovarian epithelial carcinomas through inhibiting the expression of PTEN protein. Int J Mol Med 26:819–827PubMedCrossRef

11.

Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103:2257–2261PubMedCrossRef

12.

Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, Liu S, Alder H, Costinean S, Fernandez-Cymering C, Volinia S, Guler G, Morrison CD, Chan KK, Marcucci G, Calin GA, Huebner K, Croce CM (2007) MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA 104:15805–15810PubMedCrossRef

13.

Garzon R, Liu S, Fabbri M, Liu Z, Heaphy CE, Callegari E, Schwind S, Pang J, Yu J, Muthusamy N, Havelange V, Volinia S, Blum W, Rush LJ, Perrotti D, Andreeff M, Bloomfield CD, Byrd JC, Chan K, Wu LC, Croce CM, Marcucci G (2009) MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 113:6411–6418PubMedCrossRef

14.

Sato N, Tsunoda H, Nishida M, Morishita Y, Takimoto Y, Kubo T, Noguchi M (2000) Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res 60:7052–7056PubMed

15.

Ho CM, Lin MC, Huang SH, Huang CJ, Lai HC, Chien TY, Chang SF (2009) PTEN promoter methylation and LOH of 10q22-23 locus in PTEN expression of ovarian clear cell adenocarcinomas. Gynecol Oncol 112:307–313PubMedCrossRef

16.

Tam KF, Liu VW, Liu SS, Tsang PC, Cheung AN, Yip AM, Ngan HY (2007) Methylation profile in benign, borderline and malignant ovarian tumors. J Cancer Res Clin Oncol 133:331–341PubMedCrossRef

17.

Kang YH, Lee HS, Kim WH (2002) Promoter methylation and silencing of PTEN in gastric carcinoma. Lab Invest 82:285–291PubMedCrossRef

18.

Marsit CJ, Zheng S, Aldape K, Hinds PW, Nelson HH, Wiencke JK, Kelsey KT (2005) PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum Pathol 36:768–776PubMedCrossRef

19.

Baouendi M, Cognet JA, Ferreira CS, Missailidis S, Coutant J, Piotto M, Hantz E, du Penhoat CH (2011) Solution structure of a truncated anti-MUC1 DNA aptamer determined by mesoscale modeling and NMR. FEBS J. doi:10.1111/j.1742-4658.2011.08440.x

20.

McNamara JO 2nd, Andrechek ER, Wang Y, Viles KD, Rempel RE, Gilboa E, Sullenger BA, Giangrande PH (2006) Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat Biotechnol 24:1005–1015PubMedCrossRef

21.

Ni X, Zhang Y, Ribas J, Chowdhury WH, Castanares M, Zhang Z, Laiho M, DeWeese TL, Lupold SE (2011) Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts. J Clin Invest 121:2383–2390PubMedCrossRef

22.

23.

Hisatsune A, Kawasaki M, Nakayama H, Mikami Y, Miyata T, Isohama Y, Katsuki H, Kim KC (2009) Internalization of MUC1 by anti-MUC1 antibody from cell membrane through the macropinocytotic pathway. Biochem Biophys Res Commun 388:677–682PubMedCrossRef

24.

Hisatsune A, Nakayama H, Kawasaki M, Horie I, Miyata T, Isohama Y, Kim KC, Katsuki H (2011) Anti-MUC1 antibody inhibits EGF receptor signaling in cancer cells. Biochem Biophys Res Commun 405:377–381PubMedCrossRef

25.

Kinlough CL, Poland PA, Bruns JB, Harkleroad KL, Hughey RP (2004) MUC1 membrane trafficking is modulated by multiple interactions. J Biol Chem 279:53071–53077PubMedCrossRef

26.

Constantinou PE, Danysh BP, Dharmaraj N, Carson DD (2011) Transmembrane mucins as novel therapeutic targets. Expert Rev Endocrinol Metab 6:835–848PubMedCrossRef

27.

Van Elssen CH, Frings PW, Bot FJ, Van de Vijver KK, Huls MB, Meek B, Hupperets P, Germeraad WT, Bos GM (2010) Expression of aberrantly glycosylated mucin-1 in ovarian cancer. Histopathology 57:597–606PubMedCrossRef

28.

Ferreira CS, Matthews CS, Missailidis S (2006) DNA aptamers that bind to MUC1 tumour marker: design and characterization of MUC1-binding single-stranded DNA aptamers. Tumour Biol 27:289–301PubMedCrossRef

29.

Yu C, Hu Y, Duan J, Yuan W, Wang C, Xu H, Yang XD (2011) Novel aptamer-nanoparticle bioconjugates enhances delivery of anticancer drug to MUC1-positive cancer cells in vitro. PLoS One 6:e24077PubMedCrossRef

30.

Lee S, Choi EJ, Jin C, Kim DH (2005) Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol Oncol 97:26–34PubMedCrossRef

31.

Zhang X, Kon T, Wang H, Li F, Huang Q, Rabbani ZN, Kirkpatrick JP, Vujaskovic Z, Dewhirst MW, Li CY (2004) Enhancement of hypoxia-induced tumor cell death in vitro and radiation therapy in vivo by use of small interfering RNA targeted to hypoxia-inducible factor-1alpha. Cancer Res 64:8139–8142PubMedCrossRef

32.

Zhu X, Li T, Peng S, Zhang X (2010) Maternal deprivation-caused behavioral abnormalities in adult rats relate to a non-methylation-regulated D2 receptor levels in the nucleus accumbens. Behav Brain Res 209:281–288PubMedCrossRef

33.

Brayman M, Thathiah A, Carson DD (2004) MUC1: a multifunctional cell surface component of reproductive tissue epithelia. Reprod Biol Endocrinol 2:4PubMedCrossRef

34.

Oliveira AM, Ross JS, Fletcher JA (2005) Tumor suppressor genes in breast cancer: the gatekeepers and the caretakers. Am J Clin Pathol 124:S16–S28PubMed

35.

Simon JA, Lange CA (2008) Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res 647:21–29PubMedCrossRef

36.

Trasler JM (2009) Epigenetics in spermatogenesis. Mol Cell Endocrinol 306:33–36PubMedCrossRef

37.

Carracedo A, Alimonti A, Pandolfi PP (2011) PTEN level in tumor suppression: how much is too little? Cancer Res 71:629–633PubMedCrossRef

Title: Anticancer role of MUC1 aptamer–miR-29b chimera in epithelial ovarian carcinoma cells through regulation of PTEN methylation
Authors: Furong Dai
Yi Zhang
Xin Zhu
Nianchun Shan
Yuxiang Chen
Publication date: 01-12-2012
Publisher: Springer-Verlag
Published in: Targeted Oncology / Issue 4/2012
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI: https://doi.org/10.1007/s11523-012-0236-7

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