Department of Orthopedic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
PLoS One. 2012;7(3):e33778. doi: 10.1371/journal.pone.0033778. Epub 2012 Mar 21.
MicroRNAs (miRNAs) are a class of endogenously expressed, small noncoding RNAs, which suppress its target mRNAs at the post-transcriptional level. Studies have demonstrated that miR-34a, which is a direct target of the p53 tumor suppressor gene, functions as a tumor suppressor and is associated with the tumor growth and metastasis of various human malignances. However, the role of miR-34a in osteosarcoma has not been totally elucidated. In the present study, the effects of miR-34a on osteosarcoma and the possible mechanism by which miR-34a affected the tumor growth and metastasis of osteosarcoma were investigated.
METHODOLOGY/PRINCIPAL FINDING: Over-expression of miR-34a partially inhibited proliferation, migration and invasion of osteosarcoma cells in vitro, as well as the tumor growth and pulmonary metastasis of osteosarcoma cells in vivo. c-Met is a target of miR-34a, and regulates the migration and invasion of osteosarcoma cells. Osteosarcoma cells over-expressing miR-34a exhibited a significant decrease in the expression levels of c-Met mRNA and protein simultaneously. Finally, the results from bioinformatics analysis demonstrated that there were multiple putative targets of miR-34a that may be associated with the proliferation and metastasis of osteosarcoma, including factors in Wnt and Notch signaling pathways.
CONCLUSION/SIGNIFICANCE: The results presented in this study demonstrated that over-expression of miR-34a could inhibit the tumor growth and metastasis of osteosarcoma probably through down regulating c-Met. And there are other putative miR-34a target genes beside c-Met which could potentially be key players in the development of osteosarcoma. Since pulmonary metastases are responsible for mortality of patient carrying osteosarcoma, miR-34a may prove to be a promising gene therapeutic agent. It will be interesting to further investigate the mechanism by which miR-34a functions as a tumor suppressor gene in osteosarcoma.
MicroRNAs（miRNAs）是一类内源性表达的小非编码 RNA，可在转录后水平抑制其靶 mRNA。研究表明，miR-34a 是 p53 肿瘤抑制基因的直接靶标，作为一种肿瘤抑制因子，与多种人类恶性肿瘤的生长和转移有关。然而，miR-34a 在骨肉瘤中的作用尚未完全阐明。本研究探讨了 miR-34a 对骨肉瘤的影响及其影响骨肉瘤生长和转移的可能机制。
方法/主要发现：过表达 miR-34a 可部分抑制骨肉瘤细胞的体外增殖、迁移和侵袭，以及骨肉瘤细胞的体内肿瘤生长和肺转移。c-Met 是 miR-34a 的靶标，调节骨肉瘤细胞的迁移和侵袭。过表达 miR-34a 的骨肉瘤细胞同时显著降低 c-Met mRNA 和蛋白的表达水平。最后，生物信息学分析的结果表明，miR-34a 有多个可能与骨肉瘤增殖和转移相关的潜在靶标，包括 Wnt 和 Notch 信号通路中的因子。
结论/意义：本研究结果表明，过表达 miR-34a 可能通过下调 c-Met 抑制骨肉瘤的生长和转移。除 c-Met 之外，miR-34a 可能还有其他潜在的靶基因，这些基因可能是骨肉瘤发生的关键因素。由于肺转移是骨肉瘤患者死亡的主要原因，miR-34a 可能成为一种很有前途的基因治疗药物。进一步研究 miR-34a 作为骨肉瘤肿瘤抑制基因的作用机制将是有趣的。
Zotero 插件
