Systematic interrogation of 3q26 identifies TLOC1 and SKIL as cancer drivers.
Systematic interrogation of 3q26 identifies TLOC1 and SKIL as cancer drivers.
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DOI：
10.1158/2159-8290.cd-12-0592
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发表时间：
2013-09
期刊：
影响因子：
28.2
通讯作者：
Hahn WC
中科院分区：
文献类型：
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作者：
Hagerstrand D;Tong A;Schumacher SE;Ilic N;Shen RR;Cheung HW;Vazquez F;Shrestha Y;Kim SY;Giacomelli AO;Rosenbluh J;Schinzel AC;Spardy NA;Barbie DA;Mermel CH;Weir BA;Garraway LA;Tamayo P;Mesirov JP;Beroukhim R;Hahn WC
3q26在几种癌症类型中经常扩增，具有包含20个基因的共同扩增区域。为了确定该区域的癌症驱动基因，我们通过功能丧失和获得遗传筛选来询问这些基因中的每一个的功能。具体而言，我们发现TLOC 1（SEC62）是选择性地需要与3q26扩增的细胞系的增殖。增加TLOC 1表达诱导锚定非依赖性生长和第二个3q26基因，SKIL（SNON），促进细胞侵袭永生化的人乳腺上皮细胞。TLOC 1和SKIL的表达诱导皮下肿瘤生长。蛋白质组学研究表明，TLOC 1结合DDX3X，这是TLOC 1诱导的转化和影响蛋白质翻译所必需的。SKIL通过上调SLUG（SNAI2）表达诱导侵袭。总之，这些研究确定TLOC 1和SKIL作为3q26的驱动基因，更广泛地表明，合作基因可能在其他区域与体细胞拷贝数增益共扩增。
3q26 is frequently amplified in several cancer types with a common amplified region containing 20 genes. To identify cancer driver genes in this region, we interrogated the function of each of these genes by loss- and gain-of-function genetic screens. Specifically, we found that TLOC1 (SEC62) was selectively required for the proliferation of cell lines with 3q26 amplification. Increased TLOC1 expression induced anchorage independent growth and a second 3q26 gene, SKIL (SNON), facilitated cell invasion in immortalized human mammary epithelial cells. Expression of both TLOC1 and SKIL induced subcutaneous tumor growth. Proteomic studies demonstrated that TLOC1 binds to DDX3X, which is essential for TLOC1-induced transformation and affected protein translation. SKIL induced invasion through up-regulation of SLUG (SNAI2) expression. Together, these studies identify TLOC1 and SKIL as driver genes at 3q26 and more broadly suggest that cooperating genes may be co-amplified in other regions with somatic copy number gain.