1Departments of Medical Oncology and 2Cancer Biology; 3Center for Cancer Genome Discovery, Dana-Farber Cancer Institute;4Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; 5Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and 6Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina.
Cancer Discov. 2013 Sep;3(9):1044-57. doi: 10.1158/2159-8290.CD-12-0592. Epub 2013 Jun 13.
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 showed that TLOC1 binds to DDX3X, which is essential for TLOC1-induced transformation and affected protein translation. SKIL induced invasion through upregulation 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 coamplified in other regions with somatic copy number gain.
These studies identify TLOC1 and SKIL as driver genes in 3q26. These observations provide evidence that regions of somatic copy number gain may harbor cooperating genes of different but complementary functions.
3q26 在几种癌症类型中经常被扩增，常见的扩增区域包含 20 个基因。为了鉴定该区域中的癌症驱动基因，我们通过基因敲除和过表达遗传筛选来研究这些基因的功能。具体来说，我们发现 TLOC1（SEC62）是携带 3q26 扩增的细胞系增殖所必需的。TLOC1 表达的增加诱导了无锚定依赖性生长，并且第二个 3q26 基因 SKIL（SNON）促进了永生化人乳腺上皮细胞的侵袭。TLOC1 和 SKIL 的表达均诱导皮下肿瘤生长。蛋白质组学研究表明，TLOC1 与 DDX3X 结合，DDX3X 对于 TLOC1 诱导的转化是必需的，并影响蛋白质翻译。SKIL 通过上调 SLUG（SNAI2）的表达诱导侵袭。总之，这些研究鉴定了 TLOC1 和 SKIL 为 3q26 的驱动基因，并更广泛地表明，在具有体细胞拷贝数增益的其他区域中，可能共扩增了具有不同但互补功能的合作基因。
这些研究鉴定了 TLOC1 和 SKIL 为 3q26 的驱动基因。这些观察结果提供了证据，表明体细胞拷贝数增益区域可能包含具有不同但互补功能的合作基因。
