体外肿瘤抑制分子MicroRNA

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这篇由Yong Sun Lee和Anindya Dutta联合发表在4月16日《Genes & development》杂志上的文章表明，microRNA在体外可以作为肿瘤抑制分子起作用。

  “在许多医学上重要的肿瘤中，如子宫肌瘤，HMGA2都会过量表达，这是一个重要的特征。” Dutta介绍说，“这确实是一个令人称奇的发现，microRNA竟然可以抑制HMGA2的过量表达。这项发现可能有助于我们理解microRNA在肿瘤发生过程中的作用，并可能为此类疾病的治疗提供思路。”

  在研究染色体上HMGA2易位的过程中，研究者发现在正常的细胞中，被称作let-7的microRNA会结合HMGA2 mRNA转录产物的3’端，并抑制该基因在细胞胞浆中的表达。如果将HMGA2转录产物的3’端缩短，阻止let-7的结合，会导致HMGA2的过量表达，这种紊乱表达也引起了肿瘤的发生。此项研究成果表明HMGA2是let-7的靶标，而且let-7作为肿瘤抑制分子阻碍着健康细胞中癌症的发生。

部分英文原文：
Published online before print April 16, 2007
Genes and Development, DOI: 10.1101/gad.1540407

Yong Sun Lee and Anindya Dutta1

Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908, USA


HMGA2, a high-mobility group protein, is oncogenic in a variety of tumors, including benign mesenchymal tumors and lung cancers. Knockdown of Dicer in HeLa cells revealed that the HMGA2 gene is transcriptionally active, but its mRNA is destabilized in the cytoplasm through the microRNA (miRNA) pathway. HMGA2 was derepressed upon inhibition of let-7 in cells with high levels of the miRNA. Ectopic expression of let-7 reduced HMGA2 and cell proliferation in a lung cancer cell. The effect of let-7 on HMGA2 was dependent on multiple target sites in the 3' untranslated region (UTR), and the growth-suppressive effect of let-7 on lung cancer cells was rescued by overexpression of the HMGA2 ORF without a 3'UTR. Our results provide a novel example of suppression of an oncogene by a tumor-suppressive miRNA and suggest that some tumors activate the oncogene through chromosomal translocations that eliminate the oncogene’s 3'UTR with the let-7 target sites.


[Keywords: let-7; microRNA; HMGA2; lung cancer]

1 Corresponding author.

E-MAIL ad8q@virginia.edu ; FAX (434) 924-5069.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1540407