PVT1 dependence in cancer with MYC copy-number increase.
PVT1 dependence in cancer with MYC copy-number increase.
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DOI：
10.1038/nature13311
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发表时间：
2014-08-07
期刊：
影响因子：
64.8
通讯作者：
Bagchi A
中科院分区：
文献类型：
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作者：
Tseng YY;Moriarity BS;Gong W;Akiyama R;Tiwari A;Kawakami H;Ronning P;Reuland B;Guenther K;Beadnell TC;Essig J;Otto GM;O'Sullivan MG;Largaespada DA;Schwertfeger KL;Marahrens Y;Kawakami Y;Bagchi A
8q24.21染色体区域的额外拷贝的“获得”已被证明在许多人类癌症中是常见的，并且与不良预后相关。充分表征的髓细胞瘤病（MYC）癌基因位于8q24.21区域，并始终与包含长非编码RNA基因PVT1、CCDC26基因候选物和GSDMC基因的约2兆碱基的相邻“基因沙漠”共同获得。这些基因中的一个或多个的低拷贝数获得是否驱动肿瘤形成尚不清楚。在这里，我们在小鼠中使用染色体工程来表明，Myc基因或包含Pvt1，Ccdc26和Gsdmc的区域的单个额外拷贝不能显著地促进癌症，而包含所有四个基因的单个额外片段成功地促进癌症。在8q24扩增的人癌细胞中，获得PVT1长非编码RNA表达是高MYC蛋白水平所必需的。PVT1 RNA和MYC蛋白表达在原发性人类肿瘤中相关，并且PVT1的拷贝数在超过98%的MYC拷贝增加的癌症中共同增加。从MYC驱动的结肠癌细胞系HCT 116中消融PVT1降低了其致瘤效力。由于MYC蛋白对小分子抑制是难治的，因此高MYC蛋白水平对PVT1长非编码RNA的依赖性提供了急需的治疗靶标。
‘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 myelocytomatosis (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.