MicroRNA与DNA修复基因的关闭相关联

新的研究首次显示了MicroRNA的能够沉默基因，从而保护基因组免于致癌突变。

此项研究由俄亥俄州立大学综合癌症中心－Arthur G. James肿瘤医院和Richard J. Solove研究所研究人员所主持，结果表明，MicroRNA - 155（miR- 155）能够抑制某些基因的活性，这些基因通常能修复错误DNA配对所致的损伤。

这些基因的丢失或者沉默被称为错配修复基因，导致遗传性癌症易感综合征，并促进大肠癌、子宫癌、卵巢癌和其他癌症的恶化。

“这是第一个证据表明，MicroRNA的失调可能导致基因组不稳定，这是癌症细胞的一个特点，”主要研究员Carlo M. Croce医生，分子病毒学、免疫学和医学遗传学教授，同时是美国俄亥俄州立的人类癌症遗传学主任。

“我们发现，miR-155主要作用和下调错配修复基因，miR – 155高表达引起基因组改变的增加，这促进癌症的发生，”他说。

这项研究发表在最新一期的美国国家科学院院刊（PNAS），显示如下：

在一个大肠癌细胞株中，过表达miR－155表达分别降低了人类错配修复基因MLH1、MSH2和MSH6表达的672﹪，42﹪和69﹪。

高表达miR - 155 和MSH2和MLH1基因的低表达存在相关性。

人类肿瘤以错配修复功能不明为特征，显示miR- 155过表达。 第三个发现可能解释一个结肠癌症难题。约百分之五的患者以微卫星标记不稳定为特征，提示丧失错配修复能力，存在癌症的易患性。这些病例没有显示出错配基因的表达。然而，基因本身没有改变不能解释表达的丧失。

“这项研究描述了一种全新的机制，或许可以解释大肠癌患者表现的微卫星不稳定性，但没有错配基因的突变或失活，”共同作者Muller Fabbr说，他是一位俄亥俄州立大学综合癌症中心科学家。

总体而言，Croce说，“我们的发现表明，miR- 155的表达可能是癌症病人的预后和治疗的重要因素，当标准检测不能提供一个决定性的诊断时，它提供了一个另外的分析方法，来研究探索微卫星不稳定肿瘤的病因。”

研究经费来自国家癌症研究所，国家医学科学院，意大利里Ricerca sul Cancro研究所资助了这项研究。

其他俄亥俄州参与这项研究的研究人员：Nicola Valeri, Pierluigi Gasparini, Chiara Braconi, Angelo Veronese, Francesca Lovat, Brett Adair, Arianna Bottoni, Stefan Costinean, Sukhinder K. Sandhu, Gerard J Nuovo, Hansjuerg Alder, Federica Calore, Stefano Volinia, Michael A. McIlhatton and Richard Fishel。       Croce是John W. Wolfe人类癌症遗传学主席。点击此处参与论坛讨论

MicroRNA Linked To Shut-Down Of DNA-Repair Genes

New research shows for the first time that molecules called microRNA can silence genes that protect the genome from cancer-causing mutations.The study, led by researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, shows that microRNA-155 (miR-155) can inhibit the activity of genes that normally correct the damage when the wrong bases are paired in DNA.The loss or silencing of these genes, which are called mismatch repair genes, causes inherited cancer-susceptibility syndromes and contributes to the progression of colorectal, uterine, ovarian and other cancers."This is the first evidence that deregulation of microRNAs can cause genomic instability, a characteristic of cancer cells," says principal investigator Dr. Carlo M. Croce, professor of molecular virology, immunology and medical genetics, and director of Ohio State's Human Cancer Genetics program."We discovered that miR-155 targets and downregulates mismatch repair genes and that overexpression of miR-155 results in an increase in genomic alterations that contribute to cancer pathogenesis," he says.The study was published recently in the Proceedings of the National Academy of Sciences and shows the following: Overexpression of miR-155 reduced the expression of the human mismatch repair genes MLH1, MSH2 and MSH6 by 72 percent, 42 percent and 69 percent, respectively, in a colorectal cancer cell line.High expression of miR-155 in human colorectal tumors correlates with low expression of MLH1 and MSH2.Human tumors that feature unexplained mismatch repair inactivation showed miR-155 overexpression. The third finding may explain a colon-cancer conundrum. About five percent of colorectal cancer cases feature a genomic marker called microsatellite instability that signals the loss of mismatch repair ability and the presence of an inherited cancer predisposition condition. These cases also show no expression of mismatch genes. Yet, the genes themselves show no alterations that explain the loss of expression."This study describes a totally new mechanism that might explain those cases of colorectal cancer that display microsatellite instability but no mutations or epigenetic inactivation of the mismatch repair genes," says co-author Muller Fabbri, a research scientist with the OSUCCC-James.Overall, Croce says, "Our findings suggest that miR-155 expression might be an important stratification factor in the prognosis and treatment of cancer patients and provide an additional analytical test for exploring the etiology of microsatellite-instability tumors when the standard tests do not provide a conclusive diagnosis."Funding from the National Cancer Institute, National Institute of General Medical Sciences and Associazione Italiana Ricerca sul Cancro supported this research.Other Ohio State researchers involved in this study were Nicola Valeri, Pierluigi Gasparini, Chiara Braconi, Angelo Veronese, Francesca Lovat, Brett Adair, Arianna Bottoni, Stefan Costinean, Sukhinder K. Sandhu, Gerard J Nuovo, Hansjuerg Alder, Federica Calore, Stefano Volinia, Michael A. McIlhatton and Richard Fishel.Croce is the John W. Wolfe Chair in Human Cancer Genetics.Source: Darrell E. WardOhio State University Medical Center