Genetically engineered pre-microRNA-34a prodrug suppresses orthotopic osteosarcoma xenograft tumor growth via the induction of apoptosis and cell cycle arrest
نویسندگان
چکیده
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.
منابع مشابه
MicroRNA-34a promotes cell cycle arrest and apoptosis and suppresses cell adhesion by targeting DUSP1 in osteosarcoma.
MicroRNAs are often deregulated in most cancer types and have important functions in carcinogenesis and cancer progression. Here, we studied the function of microRNA-34 (miR-34a) in osteosarcoma MG63 and U-2OS cells by expressed with pre-miR-34a, anti-miR-34a and corresponding negative controls, respectively. Cells proliferation, cell cycle and apoptosis was measured by MTT and flow cytometry a...
متن کاملSulforaphane induces cell cycle arrest and apoptosis in murine osteosarcoma cells in vitro and inhibits tumor growth in vivo.
Sulforaphane (SFN), a naturally occurring isothiocyanate, is an attractive agent due to its potent anticancer effects. SFN suppresses the proliferation of various cancer cells in vitro and in vivo. In this study, we report that SFN inhibited the proliferation of cultured murine osteosarcoma LM8 cells. Twenty micromolar SFN completely inhibited the growth of LM8 cells and caused G2/M-phase arres...
متن کاملKnockdown of TRAF4 expression suppresses osteosarcoma cell growth in vitro and in vivo.
Tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) is an adapter molecule that is overexpressed in certain cancers. TRAF4 is overexpressed in osteosarcoma tissues and osteosarcoma cells. Using the technique of RNA interference, the expression of TRAF4 in the human osteosarcoma Saos-2 cell line was shown to be downregulated. The proliferation, cell cycle arrest and apoptosis abilit...
متن کاملTumor suppressor microRNA-34a inhibits cell proliferation by targeting Notch1 in renal cell carcinoma
MicroRNA-34a (miR-34a) is a tumor suppressive microRNA, which induces G1 arrest, apoptosis and senescence by repressing the expression of multiple oncogenes. This study aimed to investigate the biological function and molecular mechanisms of miR-34a in human renal cell carcinoma (RCC) cells. Quantitative polymerase chain reaction (qPCR) revealed that miR-34a expression was significantly downreg...
متن کاملMicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1.
Endothelial progenitor cells (EPCs) play an important role in angiogenesis, which is essential for numerous physiological processes as well as tumor growth. Several microRNAs (miRNAs) have been reported to be involved in angiogenesis. MiR-34a, recently reported as a tumor suppressor, has been found to target silent information regulator 1 (Sirt1), leading to cell cycle arrest or apoptosis. Howe...
متن کامل