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Synthetic siRNA targeting the breakpoint of EWS/Fli-1 inhibits growth of Ewing sarcoma xenografts in a mouse model.
Int J Cancer. 2011 Jan 01; 128(1):216-26.IJ

Abstract

The EWS/Fli-1 fusion gene, a product of the translocation t(11;22, q24;q12), is detected in 85% of Ewing sarcomas and primitive neuroectodermal tumors. It is thought to be a transcriptional activator that plays a significant role in tumorigenesis. In this study, we developed a novel EWS/Fli-1 blockade system using RNA interference and tested its application for inhibiting the proliferation of Ewing sarcoma cells in vitro and the treatment of mouse tumor xenografts in vivo. We designed and synthesized a small interfering RNA (siRNA) possessing an aromatic compound at the 3'-end targeting the breakpoint of EWS/Fli-1. As this sequence is present only in tumor cells, it is a potentially relevant target. We found that the siRNA targeting EWS/Fli-1 significantly suppressed the expression of EWS/Fli-1 protein sequence specifically and also reduced the expression of c-Myc protein in Ewing sarcoma cells. We further demonstrated that inhibition of EWS/Fli-1 expression efficiently inhibited the proliferation of the transfected cells but did not induce apoptotic cell death. In addition, the siRNA possessing the aromatic compound at the 3'-end was more resistant to nucleolytic degradation than the unmodified siRNA. Administration of the siRNA with atelocollagen significantly inhibited the tumor growth of TC-135, a Ewing sarcoma cell line, which had been subcutaneously xenografted into mice. Moreover, modification of the 3'-end with an aromatic compound improved its efficiency in vivo. Our data suggest that specific downregulation of EWS/Fli-1 by RNA interference is a possible approach for the treatment of Ewing sarcoma.

Authors+Show Affiliations

Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20648560

Citation

Takigami, Iori, et al. "Synthetic siRNA Targeting the Breakpoint of EWS/Fli-1 Inhibits Growth of Ewing Sarcoma Xenografts in a Mouse Model." International Journal of Cancer, vol. 128, no. 1, 2011, pp. 216-26.
Takigami I, Ohno T, Kitade Y, et al. Synthetic siRNA targeting the breakpoint of EWS/Fli-1 inhibits growth of Ewing sarcoma xenografts in a mouse model. Int J Cancer. 2011;128(1):216-26.
Takigami, I., Ohno, T., Kitade, Y., Hara, A., Nagano, A., Kawai, G., Saitou, M., Matsuhashi, A., Yamada, K., & Shimizu, K. (2011). Synthetic siRNA targeting the breakpoint of EWS/Fli-1 inhibits growth of Ewing sarcoma xenografts in a mouse model. International Journal of Cancer, 128(1), 216-26. https://doi.org/10.1002/ijc.25564
Takigami I, et al. Synthetic siRNA Targeting the Breakpoint of EWS/Fli-1 Inhibits Growth of Ewing Sarcoma Xenografts in a Mouse Model. Int J Cancer. 2011 Jan 1;128(1):216-26. PubMed PMID: 20648560.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthetic siRNA targeting the breakpoint of EWS/Fli-1 inhibits growth of Ewing sarcoma xenografts in a mouse model. AU - Takigami,Iori, AU - Ohno,Takatoshi, AU - Kitade,Yukio, AU - Hara,Akira, AU - Nagano,Akihito, AU - Kawai,Gou, AU - Saitou,Mitsuru, AU - Matsuhashi,Aya, AU - Yamada,Kazunari, AU - Shimizu,Katsuji, PY - 2010/7/22/entrez PY - 2010/7/22/pubmed PY - 2010/12/31/medline SP - 216 EP - 26 JF - International journal of cancer JO - Int J Cancer VL - 128 IS - 1 N2 - The EWS/Fli-1 fusion gene, a product of the translocation t(11;22, q24;q12), is detected in 85% of Ewing sarcomas and primitive neuroectodermal tumors. It is thought to be a transcriptional activator that plays a significant role in tumorigenesis. In this study, we developed a novel EWS/Fli-1 blockade system using RNA interference and tested its application for inhibiting the proliferation of Ewing sarcoma cells in vitro and the treatment of mouse tumor xenografts in vivo. We designed and synthesized a small interfering RNA (siRNA) possessing an aromatic compound at the 3'-end targeting the breakpoint of EWS/Fli-1. As this sequence is present only in tumor cells, it is a potentially relevant target. We found that the siRNA targeting EWS/Fli-1 significantly suppressed the expression of EWS/Fli-1 protein sequence specifically and also reduced the expression of c-Myc protein in Ewing sarcoma cells. We further demonstrated that inhibition of EWS/Fli-1 expression efficiently inhibited the proliferation of the transfected cells but did not induce apoptotic cell death. In addition, the siRNA possessing the aromatic compound at the 3'-end was more resistant to nucleolytic degradation than the unmodified siRNA. Administration of the siRNA with atelocollagen significantly inhibited the tumor growth of TC-135, a Ewing sarcoma cell line, which had been subcutaneously xenografted into mice. Moreover, modification of the 3'-end with an aromatic compound improved its efficiency in vivo. Our data suggest that specific downregulation of EWS/Fli-1 by RNA interference is a possible approach for the treatment of Ewing sarcoma. SN - 1097-0215 UR - https://www.unboundmedicine.com/medline/citation/20648560/Synthetic_siRNA_targeting_the_breakpoint_of_EWS/Fli_1_inhibits_growth_of_Ewing_sarcoma_xenografts_in_a_mouse_model_ L2 - https://doi.org/10.1002/ijc.25564 DB - PRIME DP - Unbound Medicine ER -