来自冷泉港实验室，霍华休斯医学院，德国汉诺威医学院胃肠病学和肝脏学系，中国香港大学医学院外科系，德国海德堡大学医学院病理学系的科学家联手通过RNAi技术鉴定出12个新的癌症抑制基因，最新的成果发表在Cell online。
癌症的发生是一个复杂的过程，多种内外环境的改变涉及其中，最受关注的莫过于遗传物质的改变即基因突变。尽管科学家投入了大量的心血在癌症基因组的研究上，但是迄今为止，并没有全面了解癌症的发生机制，涉及癌症发生的基因也没有完全了解透彻。到目前为止已知的参与抑制癌症的基因有p53,p15,p16,p21等。
冷泉港的科学家为了研究抑制癌症发生的基因，构建了肝癌模型小鼠，并设计一个shRNA库，用RNAi技术抑制这些靶位基因， 以期获得新的抑癌基因资料。在选择shRNA方面，研究小组将人类肝癌细胞里发生改变的100个基因列入其中，因此，与随机的RNAi筛选相比，这一方法可更有针对性的筛选出与癌症有关的基因。
通过进一步的研究，科研小组鉴定出13个肿瘤抑制基因，其中有1个基因是先前已经发现的抑癌基因，另外的12个是新发现的抑癌基因。其中，XPO4基因编码核输出蛋白，是EIF5A2的作用底物，该基因在肿瘤细胞中被过度表达，它是XPO4缺陷的肿瘤细胞增殖必须的因子，可促进肝癌细胞生长。
研究小组认为，通过人类癌细胞建立的shRNA库技术结合癌症模型技术可在基因组水平筛选出更多的抑癌基因。研究者希望将这一技术延伸到其他癌症基因组的研究上。（生物谷Bioon.com）
生物谷推荐原始出处：
Cell, 13 November 2008 doi:10.1016/j.cell.2008.09.061
An Oncogenomics-Based In Vivo RNAi Screen Identifies Tumor Suppressors in Liver Cancer
Lars Zender1,6,7,Wen Xue1,7,Johannes Zuber1,Camile P. Semighini1,Alexander Krasnitz1,Beicong Ma1,Peggy Zender1,Stefan Kubicka3,John M. Luk4,Peter Schirmacher5,W. Richard McCombie1,Michael Wigler1,James Hicks1,Gregory J. Hannon1,2,Scott Powers1andScott W. Lowe1,2,,
1 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
2 Howard Hughes Medical Institute, Cold Spring Harbor, New York 11724, USA
3 Department of Gastroenterology and Hepatology, Medical School Hannover, 30625 Hannover, Germany
4 Department of Surgery, University of Hong Kong, Hong Kong, China
5 Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany
6 Present address: Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany and Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, 30625 Hannover, Germany
7 These authors contributed equally to this work
SUMMARY
Cancers are highly heterogeneous and contain many passenger and driver mutations. To functionally identify tumor suppressor genes relevant to human cancer, we compiled pools of short hairpin RNAs (shRNAs) targeting the mouse orthologs of genes recurrently deleted in a series of human hepatocellular carcinomas and tested their ability to promote tumorigenesis in a mosaic mouse model. In contrast to randomly selected shRNA pools, many deletion-specific pools accelerated hepatocarcinogenesis in mice. Through further analysis, we identified and validated 13 tumor suppressor genes, 12 of which had not been linked to cancer before. One gene, XPO4, encodes a nuclear export protein whose substrate, EIF5A2, is amplified in human tumors, is required for proliferation of XPO4-deficient tumor cells, and promotes hepatocellular carcinoma in mice. Our results establish the feasibility of invivo RNAi screens and illustrate how combining cancer genomics, RNA interference, and mosaic mouse models can facilitate the functional annotation of the cancer genome.
