let-7 microRNA ：本质上延缓肺癌生长

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A MicroRNA Molecule Can Reduce Lung Cancer Growth, Study Shows

ScienceDaily (Mar. 23, 2008) — A small RNA molecule, known as let-7 microRNA (miRNA), substantially reduced cancer growth in multiple mouse models of lung cancer, according to work by researchers at Yale University and Asuragen, Inc., published in the journal Cell Cycle.

Cancer afflicts 1.5 million people a year in the United States alone, and lung cancer is the most common and deadly form of cancer worldwide. This study indicates a direct role for a miRNA in cancer progression and introduces a new paradigm of using miRNAs as effective therapeutic agents to treat human cancer.

\"We believe this is the first report of a miRNA being used to a beneficial effect on any cancer, let alone lung cancers, the deadliest of all cancers worldwide,\" said senior author Frank Slack, associate professor of molecular, cellular and developmental biology at Yale.

Slack's research group initially discovered the let-7 miRNA in C. elegans, a tiny worm used as a model system for studying how organisms develop, grow and age. They went on to show that in humans, let-7 negatively regulates a well-known determinant of human lung cancers, the RAS oncogene.

In collaboration with scientists at Asuragen, the Slack lab has studied the tumor suppressor activity of this small RNA. Their work revealed that let-7 is commonly present at substantially reduced levels in lung tumors -- and that reduced levels of let-7 likely contribute to the development of the tumors. These discoveries focused public attention and research efforts to understand the potential use of naturally occurring microRNAs like let-7 to combat cancer.

This new work demonstrates that let-7 inhibits the growth of lung cancer cells in culture and in lung tumors in mice. They also showed that let-7 can be applied as an intranasal drug to reduce tumor formation in a RAS mouse model lung cancer.

\"We believe that our studies provide the first direct evidence in mammals, that let-7 functions as a tumor suppressor gene,\" said Slack. \"Because multiple cell lines and mouse models of lung cancer were used, it appears that therapeutic application of let-7 may provide benefits to a broad group of lung cancer patients.\"

\"This has been a very productive industry-academic collaboration between Yale and Asuragen scientists\" commented Matt Winkler CEO of Asuragen. \"This work provides further evidence of the importance of miRNAs in the development of cancer and provides additional support for miRNA replacement therapy as an important component of effective cancer treatment regimens of the future.\"

Other authors on the paper were Aurora Esquela-Kerscher, Phong Trang and Joanne Weidhaas at Yale; Jason Wiggins, Lubna Patrawala, David Brown and Andreas Bader at Asuragen, Inc.; Angie Cheng and Lance Ford at Ambion, Inc. The work was funded by a grant from the State of Connecticut Department of Public Health and fellowships from the National Institutes of Health.
科学日报（2008-03-23）---根据耶鲁大学和Asuragen公司的研究人员刊登在细胞周期（Cell Cycle）杂志上的研究成果显示：一种名为let-7的小RNA分子（miRNA）能够有效地减缓多种肺癌小鼠模型中肿瘤的生长速度。

每年仅在美国就有150万人遭受癌症的折磨，肺癌是全球最常见和最致命的肿瘤。该研究发现了一种miRNA分子在肿瘤发展过程中的作用，并指出了利用miRNAs来作为治疗人类肿瘤的有效物质这一新的治疗方法。

“我们认为这是关于某种miRNA分子被用于肿瘤治疗的第一篇报导,更不要说是肺癌，世界最致命的肿瘤”，文章的主要作者Frank Slack, 来自耶鲁大学分子、细胞和发育生物学部的助理教授，称。

Slack的研究小组最开始在线虫，一种小蠕虫，用来研究生物发育，生长和老化的模式生物，体内发现了let-7 miRNA。接着他们在人类身上证明，let-7能够负调控肿瘤基因RAS，一种公认的重要的致癌基因。

Slack的研究人员与Asuragen公司的科学家们一起研究了该miRNA 分子的肿瘤抑制活性。他们的研究结果表明在肺部肿瘤中let-7的表达普遍很低---而且let-7表达的低水平可能有助于肿瘤的生长。研究结果引起了公众的关注，同时兴起了关于利用与let-7类似的天然小分子RNA抗肿瘤潜力相关的研究。

这项新的研究证明，let-7能够抑制培养的肺癌细胞和大鼠体内的肿瘤细胞的生长。该研究同样证明，let-7以鼻内给药的方式能够减少RAS类型小鼠肺癌模型的肿瘤形成。

“我们认为我们的研究首次直接证明了，let-7在哺乳动物体内的功能就像肿瘤抑制基因一样”Slack说，“因为实验中用到了各种细胞系和小鼠肺癌模型，而且效果都不错，似乎随着let-7应用于治疗，可能会对众多类型的肺癌患者带来福音。”

“这次耶鲁大学和Asuragen公司的科学家的合作是一次收获颇丰的商业—科研合作”Asuragen公司的总裁Matt Winkler评价说，“这次研究结果在证明小RNA分子在肿瘤发展过程中的重要性方面提供了进一步证据。同时，为将来miRNA替代疗法在肿瘤治疗方法中占有一席之地提供了额外支持。”

论文的其他作者包括：耶鲁大学的Aurora Esquela-Kerscher，Phong Trang 和 Joanne Weidhaas；Asuragen公司的Jason Wiggins, Lubna Patrawala, David Brown 和 Andreas Bader；Ambion公司的Angie Cheng 和Lance Ford。该研究受到康涅狄格州公共卫生部以及国立卫生研究院的资助。