Tumor-suppressive microRNA-let-7a inhibits cell proliferation via targeting of E2F2 in osteosarcoma cells
Tumor-suppressive microRNA-let-7a inhibits cell proliferation via targeting of E2F2 in osteosarcoma cells
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DOI：
10.3892/ijo.2015.2867
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发表时间：
2015-04-01
影响因子：
5.2
通讯作者：
Tsumura, Hiroshi
中科院分区：
文献类型：
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作者：
Iwasaki, Tatsuya;Tanaka, Kazuhiro;Tsumura, Hiroshi
MicroRNAs （miRNAs）在转录后水平上通过沉默基因表达来调节细胞增殖和分化；此外，通过与癌细胞mrna中的互补序列结合，这些小的非编码RNA分子可以作为肿瘤抑制因子或癌基因。最近，miRNA表达的失调被发现与几种癌症类型的致瘤性增加和预后不良有关，包括骨肉瘤（OS）。为了确定OS中潜在的致癌因素，我们通过微阵列方法分析了5种OS细胞系和人间充质干细胞（hMSCs）中miRNAs及其下游mrna的表达谱变化。与hMSCs相比，所有OS细胞中miRNA-let-7a的表达显著下调，E2F2的表达显著上调。将let-7a转染到OS细胞系中，细胞中E2F2的表达被显著抑制，提示E2F2是miRNA-let-7a在OS细胞中的靶标。转染let-7a进一步抑制细胞周期的进展和OS细胞的增殖。此外，let-7a在OS细胞中的过表达在体内显著抑制肿瘤生长。本研究揭示了在OS细胞中通过miRNA-let-7a调控E2F2表达的新机制。由于E2F2通过调节几个基因在促进细胞生长方面起关键作用，我们的研究结果可能有助于开发治疗OS的新治疗靶点。
MicroRNAs (miRNAs) regulate cell proliferation and differentiation by silencing gene expression at the post-transcriptional level; moreover, by binding to the complementary sequences within mRNAs in cancer cells, these small non-coding RNA molecules can function as tumor suppressors or oncogenes. Recently, the dysregulation of miRNA expression has been found to be associated with increased tumorigenicity and poor prognosis in several cancer types, including osteosarcoma (OS). To identify potential oncogenic factors in OS, we analyzed changes in the expression profile of miRNAs and its downstream mRNAs in five OS cell lines and human mesenchymal stem cells (hMSCs) by a micro-array-based approach. The expression of an miRNA-let-7a was significantly downregulated and E2F2 was significantly upregulated in all tested OS cells compared with hMSCs. When let-7a was transfected into OS cell lines, the expression of E2F2 in the cells was greatly suppressed, suggesting that E2F2 is a target of miRNA-let-7a in OS cells. The transfection of let-7a further inhibited cell cycle progression and proliferation of OS cells. In addition, let-7a overexpression in OS cells significantly suppressed the tumor growth in vivo. The present study demonstrates the novel mechanism that regulates E2F2 expression via miRNA-let-7a in OS cells. Because E2F2 is pivotal in promoting cell growth through the regulation of several genes, our results might facilitate the development of new therapeutic targets for the treatment of OS.