Genetically Engineered Pre-microRNA-34a Prodrug Suppresses Orthotopic Osteosarcoma Xenograft Tumor Growth Via the Induction of Apoptosis and Cell Cycle Arrest

Overview

Journal Sci Rep

Specialty Science

Date 2016 May 25

PMID 27216562

Citations 34

Authors

Yong Zhao

Mei-Juan Tu

Wei-Peng Wang

Jing-Xin Qiu

Ai-Xi Yu

Ai-Ming Yu

Affiliations

Soon will be listed here.

Abstract

Osteosarcoma (OS) is the most common primary malignant bone tumor in children, and microRNA-34a (miR-34a) replacement therapy represents a new treatment strategy. This study was to define the effectiveness and safety profiles of a novel bioengineered miR-34a prodrug in orthotopic OS xenograft tumor mouse model. Highly purified pre-miR-34a prodrug significantly inhibited the proliferation of human 143B and MG-63 cells in a dose dependent manner and to much greater degrees than controls, which was attributed to induction of apoptosis and G2 cell cycle arrest. Inhibition of OS cell growth and invasion were associated with release of high levels of mature miR-34a from pre-miR-34a prodrug and consequently reduction of protein levels of many miR-34a target genes including SIRT1, BCL2, c-MET, and CDK6. Furthermore, intravenous administration of in vivo-jetPEI formulated miR-34a prodrug significantly reduced OS tumor growth in orthotopic xenograft mouse models. In addition, mouse blood chemistry profiles indicated that therapeutic doses of bioengineered miR-34a prodrug were well tolerated in these animals. The results demonstrated that bioengineered miR-34a prodrug was effective to control OS tumor growth which involved the induction of apoptosis and cell cycle arrest, supporting the development of bioengineered RNAs as a novel class of large molecule therapeutic agents.

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References

Kasinski A, Slack F . miRNA-34 prevents cancer initiation and progression in a therapeutically resistant K-ras and p53-induced mouse model of lung adenocarcinoma. Cancer Res. 2012; 72(21):5576-87. PMC: 3488137. DOI: 10.1158/0008-5472.CAN-12-2001. View

Bacci G, Rocca M, Salone M, Balladelli A, Ferrari S, Palmerini E . High grade osteosarcoma of the extremities with lung metastases at presentation: treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions. J Surg Oncol. 2008; 98(6):415-20. DOI: 10.1002/jso.21140. View

Sobala A, Hutvagner G . Small RNAs derived from the 5' end of tRNA can inhibit protein translation in human cells. RNA Biol. 2013; 10(4):553-63. PMC: 3710361. DOI: 10.4161/rna.24285. View

Wang Y, Jia L, Yuan W, Wu Z, Wang H, Xu T . Low miR-34a and miR-192 are associated with unfavorable prognosis in patients suffering from osteosarcoma. Am J Transl Res. 2015; 7(1):111-9. PMC: 4346528. View

Cosco D, Cilurzo F, Maiuolo J, Federico C, Di Martino M, Cristiano M . Delivery of miR-34a by chitosan/PLGA nanoplexes for the anticancer treatment of multiple myeloma. Sci Rep. 2015; 5:17579. PMC: 4665167. DOI: 10.1038/srep17579. View

Su Y, Wagner E, Luo Q, Huang J, Chen L, He B . Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma. Oncogene. 2011; 30(37):3907-17. DOI: 10.1038/onc.2011.97. View

Gorlick R, Janeway K, Lessnick S, Randall R, Marina N . Children's Oncology Group's 2013 blueprint for research: bone tumors. Pediatr Blood Cancer. 2012; 60(6):1009-15. PMC: 4610028. DOI: 10.1002/pbc.24429. View

Zhao H, Ma B, Wang Y, Han T, Zheng L, Sun C . miR-34a inhibits the metastasis of osteosarcoma cells by repressing the expression of CD44. Oncol Rep. 2013; 29(3):1027-36. DOI: 10.3892/or.2013.2234. View

Vinall R, Ripoll A, Wang S, Pan C, DeVere White R . MiR-34a chemosensitizes bladder cancer cells to cisplatin treatment regardless of p53-Rb pathway status. Int J Cancer. 2011; 130(11):2526-38. PMC: 4568996. DOI: 10.1002/ijc.26256. View

10.

Saitoh Y, Setoguchi T, Nagata M, Tsuru A, Nakamura S, Nagano S . Combination of Hedgehog inhibitors and standard anticancer agents synergistically prevent osteosarcoma growth. Int J Oncol. 2015; 48(1):235-42. DOI: 10.3892/ijo.2015.3236. View

11.

Mirabello L, Troisi R, Savage S . Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer. 2009; 115(7):1531-43. PMC: 2813207. DOI: 10.1002/cncr.24121. View

12.

Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H . The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 2011; 17(2):211-5. PMC: 3076220. DOI: 10.1038/nm.2284. View

13.

Li B, Yang Y, Jiang S, Ni B, Chen K, Jiang L . Adenovirus-mediated overexpression of BMP-9 inhibits human osteosarcoma cell growth and migration through downregulation of the PI3K/AKT pathway. Int J Oncol. 2012; 41(5):1809-19. DOI: 10.3892/ijo.2012.1617. View

14.

Ho P, Yu A . Bioengineering of noncoding RNAs for research agents and therapeutics. Wiley Interdiscip Rev RNA. 2016; 7(2):186-97. PMC: 4769674. DOI: 10.1002/wrna.1324. View

15.

Chang T, Wentzel E, Kent O, Ramachandran K, Mullendore M, Lee K . Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell. 2007; 26(5):745-52. PMC: 1939978. DOI: 10.1016/j.molcel.2007.05.010. View

16.

Goodarzi H, Liu X, Nguyen H, Zhang S, Fish L, Tavazoie S . Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement. Cell. 2015; 161(4):790-802. PMC: 4457382. DOI: 10.1016/j.cell.2015.02.053. View

17.

Li Z, Ender C, Meister G, Moore P, Chang Y, John B . Extensive terminal and asymmetric processing of small RNAs from rRNAs, snoRNAs, snRNAs, and tRNAs. Nucleic Acids Res. 2012; 40(14):6787-99. PMC: 3413118. DOI: 10.1093/nar/gks307. View

18.

Ambros V . The functions of animal microRNAs. Nature. 2004; 431(7006):350-5. DOI: 10.1038/nature02871. View

19.

Luu H, Kang Q, Park J, Si W, Luo Q, Jiang W . An orthotopic model of human osteosarcoma growth and spontaneous pulmonary metastasis. Clin Exp Metastasis. 2005; 22(4):319-29. DOI: 10.1007/s10585-005-0365-9. View

20.

Rihani A, Van Goethem A, Ongenaert M, De Brouwer S, Volders P, Agarwal S . Genome wide expression profiling of p53 regulated miRNAs in neuroblastoma. Sci Rep. 2015; 5:9027. PMC: 4356961. DOI: 10.1038/srep09027. View