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PVT1 dependence in cancer with MYC copy-number increase

机译：随着MYC拷贝数增加，癌症中的PVT1依赖性

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摘要

'Gain' of supernumerary copies of the 8q24.21 chromosomal region has been shown to be common in many human cancers and is associated with poor prognosis. The well-characterized myelo-cytomatosis (MYC) oncogene resides in the 8q24.21 region and is consistently co-gained with an adjacent 'gene desert' of approximately 2 megabases that contains the long non-coding RNA gene PVT1, the CCDC26 gene candidate and the GSDMC gene. Whether low copy-number gain of one or more of these genes drives neoplasia is not known. Here we use chromosome engineering in mice to show that a single extra copy of either the Myc gene or the region encompassing Pvt1, Ccdc26 and Gsdmc fails to advance cancer measurably, whereas a single supernumerary segment encompassing all four genes successfully promotes cancer. Gain of PVT1 long non-coding RNA expression was required for high MYC protein levels in 8q24-amplified human cancer cells. PVT1 RNA and MYC protein expression correlated in primary human tumours, and copy number of PVT1 was co-increased in more than 98% of MYC-copy-increase cancers. Ablation of PVT1 from MYC-driven colon cancer line HCT116 diminished its tumorigenic potency. As MYC protein has been refractory to small-molecule inhibition, the dependence of high MYC protein levels on PVT1 long non-coding RNA provides a much needed therapeutic target.%很多癌细胞都携带多余版本的染色体区域8q24.21,包括致癌基因。现在,Anindya Bagchi及同事对一个附近的长非编码RNA基因PVT7(该基因倾向于被共放大)的功能进行了研究。他们通过基因工程小鼠模型发现,PVT1的过度表达因8q24.21的放大而促成高水平的M/C,同时也促成由MYC驱动的肿瘤发生。MVC和PVT7水平在人类肿瘤中也是相互关联的,说明二者之间存在类似的合作。作者提出,以PVT1为目标也许能提供一个不同的治疗策略。
机译：8q24.21染色体区域多余拷贝的“增加”已显示在许多人类癌症中很常见，并且与不良预后有关。特征明确的骨髓细胞瘤病（MYC）癌基因位于8q24.21区域，并与大约2兆碱基的相邻“基因沙漠”共同获得，其中包含长的非编码RNA基因PVT1（CCDC26基因候选物）和GSDMC基因。这些基因中的一个或多个基因的低拷贝数增加是否会驱动瘤形成尚不清楚。在这里，我们在小鼠中使用染色体工程来显示Myc基因或包含Pvt1，Ccdc26和Gsdmc的区域的单个额外副本无法可测量地推进癌症，而包含所有四个基因的单个多余部分成功地促进了癌症。在8q24扩增的人类癌细胞中，高MYC蛋白水平需要获得PVT1长的非编码RNA表达。在原发性人类肿瘤中，PVT1 RNA和MYC蛋白表达相关，在超过98％的MYC复制增加的癌症中，PVT1的拷贝数共同增加。从MYC驱动的结肠癌细胞系HCT116中消融PVT1会降低其致瘤能力。由于MYC蛋白具有抗小分子抑制作用，因此高MYC蛋白水平对PVT1长非编码RNA的依赖性提供了迫切需要的治疗靶点。％许多肿瘤都携带过多版本的染色体区域8q24.21，包括致癌现在，Anindya Bagchi和同事对一个附近的长非编码RNA基因PVT7（该基因识别被共放大）的功能进行了研究。他们通过基因工程小鼠模型发现，PVT1的过度表达因8q24.21 MVC和PVT7水平在人类肿瘤中也是相互关联的，说明两者之间存在类似的合作。作者提出，以PVT1为目标也许能提供一个不同的治疗策略。

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  • 来源
    《Nature》 |2014年第7512期|82-86a1|共6页
  • 作者

    Yuen-Yi Tseng; Branden S. Moriarity; Wuming Gong; Ryutaro Akiyama; Ashutosh Tiwari; Hiroko Kawakami; Peter Ronning; Brian Reuland; Kacey Guenther; Thomas C. Beadnell; Jaclyn Essig; George M. Otto; M. Gerard OSullivan; David A. Largaespada; Kathryn L. Schwertfeger; York Marahrens; Yasuhiko Kawakami; Anindya Bagchi;

  • 作者单位

    Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA,Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA,Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA,Center for Bio-Design, Translational Health Science and Technology Institute, Gurgaon 122016, India;

    Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA,Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA,Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA,Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA,Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

    Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA,Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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