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Downregulation of Telomerase Activity in Breast Cancer Impairs Cells Proliferation, Invasive Ability and Sensitizes Cells to Ultraviolet-Radiation and Adriamycin-Chemotherapy in Vitro

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DOI: 10.4236/abcr.2013.23014    3,057 Downloads   5,929 Views   Citations

ABSTRACT

Backgroud: Telomerase activity, mainly regulated by the human telomerase reverse transcriptase (hTERT) gene, plays critical roles in tumor growth and progression through the maintenance of telomere length and structure. Telomerase is elevated in most malignant tumors as well as in breast cancer, the ubiquitous expression of telomerase makes it a promising target for cancer therapy. With the goal of down regulating telomerase activity, RNA interference technology has been applied to specifically knockdown the hTERT gene expression in breast cancer cell line MCF-7 and MDA-MB- 231 and determine whether h TERT-specific RNA interference technology serve as an effective method of telomerase-based cancer therapy. Methods: Interfering p Super-retro-puro-hTERT-RNA and the control were transfected into breast cancer cell line MCF-7 and MDA-MB-231. The telomerase activity, cell proliferation, invasive ability and cell response to ultraviolet-radiation or adriamycin-chemotherapy in vitro were recorded in transfected, untransfeced and empty-transfected cells respectively. Results: Telomerase activity was successfully suppressed in transfected cells (P < 0.005). Decreased expression of telomerase activity was associated with reduced cell proliferation (P < 0.001), migration and invasive ability (P < 0.001) and enhanced sensitivity to ultraviolet-radiation or adriamycin-chemotherapy (P < 0.001). Conclusions: Telomerase activity down regulation inhibits breast cancer cell growth, impairs cell migration, invasion and sensitizes cancer cells to radiotherapy and chemotherapy. The hTERT-specific RNA interference technology combined with radio-therapy and/or chemotherapy may serve as an effective method of telomerase-based therapy in breast cancer.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Liu, X. , Yao, C. , Lin, Y. , Wang, S. , Zhang, H. and Wang, S. (2013) Downregulation of Telomerase Activity in Breast Cancer Impairs Cells Proliferation, Invasive Ability and Sensitizes Cells to Ultraviolet-Radiation and Adriamycin-Chemotherapy in Vitro. Advances in Breast Cancer Research, 2, 78-85. doi: 10.4236/abcr.2013.23014.

References

[1] World Health Organization International Agency, “World Health Organization International Agency for Research on Cancer,” World Cancer Report, 2011.
[2] World Health Organization, “Fact Sheet No. 297: Cancer,” 2012.
[3] G. Curigliano, G. Spitaleri, E. Pietri, et al., “Breast Cancer Vaccines: A Clinical Reality or Fairy Tale?” Annals of Oncology, Vol. 17, No. 5, 2006, pp. 750-762.
[4] P. W. Nan and J. H. Richard, “The Role of Telomerase Expression and Telomere Length Maintenance in Human and Mouse,” Journal of Clinical Immunology, Vol. 20, No. 4, 2000, pp. 257-267. doi:10.1023/A:1017223602293
[5] W. Guenther, “The Viral Origins of Telomeres and Telomerases and Their Important Role in Eukaryogenesis and Genome Maintenance,” Biosemiotics, Vol. 1, No. 2, 2008, pp. 191-206. doi:10.1007/s12304-008-9018-0
[6] M. A. Blasco, “Telomeres and Human Disease: Ageing, Cancer and Beyond,” Nature Reviews. Genetics, Vol. 6, No. 8, 2005, pp. 611-622. doi:10.1038/nrg1656
[7] J. Liu, A. Baykal, K. M. Fung, et al., “Human Telomerase Reverse Transcriptase mRNA Is Highly Expressed in Normal Breast Tissues and Down-Regulated in Ductal Carcinoma in Situ,” International Journal of Oncology, Vol. 24, No. 4, 2004, pp. 879-884.
[8] J. Beesley, H. A. Pickett, S. E. Johnatty, et al., “Functional Polymorphisms in the TERT Promoter Are Associated with Risk of Serous Epithelial Ovarian and Breast Cancers,” PLoS One, Vol. 6, No. 9, 2001, Article ID: e24987. doi:10.1371/journal.pone.0024987
[9] C. Poremba, B. Heine, R. Diallo, et al., “Telomerase as a Prognostic Marker in Breast Cancer: High-Throughput Tissue Microarray Analysis of hTERT and hTR,” Journal of Pathology, Vol. 198, No. 2, 2002, pp. 181-189. doi:10.1002/path.1191
[10] K. Mokbel and N. J. Williams, “Telomerase and Breast Cancer: From Diagnosis to Therapy,” International Journal of Surgical Investigation, Vol. 2, No. 1, 2000, pp. 85-88.
[11] K. Masutomi, E. Y. Yu, S. Khurts, et al., “Telomerase Maintains Telomere Structure in Normal Human Cells,” Cell, Vol. 114, No. 2, 2003, pp. 241-253. doi:10.1016/S0092-8674(03)00550-6
[12] P. de Souza Nascimento, G. Alves and W. Fiedler, “Telomerase Inhibition by an siRNA Directed against hTERT Leads to Telomere Attrition in HT29 Cells,” Oncology Reports, Vol. 16, No. 2, 2006, pp. 423-428.
[13] J. Li, N. Zhang, L. B. Song, et al., “Astrocyte Elevated Gene-1 Is a Novel Prognostic Marker for Breast Cancer Progression and Overall Patient Survival,” Clinical Cancer Research, Vol. 14, No. 11, 2008, pp. 3319-3326. doi:10.1158/1078-0432.CCR-07-4054
[14] R. Pallini, A. Sorrentino, F. Pierconti, et al., “Telomerase Inhibition by Stable RNA Interference Impairs Tumor Growth and Angiogenesis in Glioblastoma Xenografts,” International Journal of Cancer, Vol. 118, No. 9, 2006, pp. 2158-2167. doi:10.1002/ijc.21613
[15] N. W. Kim and F. Wu, “Advances in Quantification and Characterization of Telomerase Activity by the Telomeric Repeat Amplification Protocol,” Nucleic Acids Research, Vol. 25, No. 13, 1997, pp. 2595-2597. doi:10.1093/nar/25.13.2595
[16] H. Wege, M. S. Chui, H. T. Le, et al., “SYBR Green Real-Time Telomeric Repeat Amplification Protocol for the Rapid Quantification of Telomerase Activity,” Nucleic Acids Research, Vol. 31, No. 2, 2003, Article ID: e3-3. doi:10.1093/nar/gng003
[17] S. M. Hammond, E. Bernstein, D. Beach, et al., “An RNADirected Nuclease Mediates Post-Transcriptional Gene Silencing in Drosophila Cells,” Nature, Vol. 404, No. 6775, 2000, pp. 293-296. doi:10.1038/35005107
[18] P. D. Zamore, “RNA Interference: Listening to the Sound of Silence,” Nature Structural Biology, Vol. 8, No. 9, 2001, pp. 746-750. doi:10.1038/nsb0901-746
[19] P. Ahlquist, “RNA-Dependent RNA Polymerases, Viruses, and RNA Silencing,” Science, Vol. 296, No. 5571, 2002, pp. 1270-1273. doi:10.1126/science.1069132
[20] I. J. Macrae, K. Zhou, F. Li, et al., “Structural Basis for Double-Stranded RNA Processing by Dicer,” Science, Vol. 311, No. 5758, 2006, pp. 195-198. doi:10.1126/science.1121638
[21] L. Zou, P. Zhang, C. Luo, et al., “ShRNA-Targeted hTERT Suppress Cell Proliferation of Bladder Cancer by Inhibiting Telomerase Activity,” Cancer Chemotherapy and Pharmacology, Vol. 57, No. 3, 2006, pp. 328-334. doi:10.1007/s00280-005-0056-x
[22] K. Kurvinen, S. Syrjanen and B. Johansson, “Long-Term Suppression of Telomerase Expression in HeLa Cell Clones, Transfected with an Expression Vector Carrying siRNA Targeting hTERT mRNA,” International Journal of Oncology, Vol. 29, No. 1, 2006, pp. 279-288.
[23] A. P. Cunningham, L. G. Andrews and T. O. Tollefsbol, “Retrovirus-Mediated RNA Interference Targeting hTERT through Stable Expression of Short-Hairpin RNA,” Methods in Molecular Biology, Vol. 405, 2007, pp. 39-46. doi:10.1007/978-1-60327-070-0_5
[24] P. Phatak and A. M. Burger, “Telomerase and Its Potential for Therapeutic Intervention,” British Journal of Pharmacology, Vol. 152, No. 7, 2007, pp. 1003-1011. doi:10.1038/sj.bjp.0707374
[25] M. F. Li, M. Y. Fang and Y. Wang, “Plasmid-Mediated RNAi Targeting hTERT Inhibits Telomerase Activity in K562 Cell Line,” Zhongguo Shi Yan Xue Ye Xue Za Zhi, Vol. 16, No. 1, 2008, pp. 54-60.
[26] H. Chen, Y. Li and T. O. Tollefsbol, “Strategies Targeting Telomerase Inhibition,” Molecular Biotechnology, Vol. 41, No. 2, 2009, pp. 194-199. doi:10.1007/s12033-008-9117-9
[27] M. Nakamura, K. Masutomi, S. Kyo, et al., “Efficient Inhibition of Human Telomerase Reverse Transcriptase Expression by RNA Interference Sensitizes Cancer Cells to Ionizing Radiation and Chemotherapy,” Human Gene Therapy, Vol. 16, No. 7, 2005, pp. 859-68. doi:10.1089/hum.2005.16.859

  
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