A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival.
A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival.
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DOI：
10.1016/j.ccr.2009.03.022
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发表时间：
2009-06-02
期刊：
影响因子：
50.3
通讯作者：
Settleman J
中科院分区：
文献类型：
--
作者：
Singh A;Greninger P;Rhodes D;Koopman L;Violette S;Bardeesy N;Settleman J
K-Ras突变经常发生在上皮癌中。使用shRNAs来消耗携带K-Ras突变的肺癌和胰腺癌细胞系中的K-Ras，鉴定了两类细胞系，它们需要或不需要K-Ras来维持生存力。比较这两类癌细胞揭示了K-Ras依赖性细胞中的基因表达特征，与分化良好的上皮表型相关，这也见于原发性肿瘤。这些基因中的几个编码易降解的蛋白质，如Syk和罗恩激酶和整合素β 6，其消耗诱导上皮间充质转化（EMT）和细胞凋亡，特别是在K-Ras依赖性细胞。这些发现表明，上皮分化和肿瘤细胞的活力是相关的，EMT调节剂在“K-Ras成瘾”的癌症代表候选的治疗靶点。K-Ras是实体瘤中最常见的突变癌基因，并且当异常激活时，是有效的肿瘤引发剂。然而，K-Ras介导的肿瘤发生的关键效应子的鉴定和在这种情况下临床有效的治疗策略的开发仍然具有挑战性。我们已经发现，携带K-Ras突变的癌细胞系可以广泛地分为K-Ras依赖性和K-Ras非依赖性组。通过建立可以区分这两组的基因表达特征，我们鉴定了在K-Ras依赖性细胞中特异性上调的基因，这些基因是其生存力所必需的。因此，K-Ras依赖性特征已经揭示了在否则难以治疗的人类癌症的子集中的几个潜在治疗靶点。
K-Ras mutations occur frequently in epithelial cancers. Using shRNAs to deplete K-Ras in lung and pancreatic cancer cell lines harboring K-Ras mutations, two classes were identified—lines that do or do not require K-Ras to maintain viability. Comparing these two classes of cancer cells revealed a gene expression signature in K-Ras-dependent cells, associated with a well-differentiated epithelial phenotype, which was also seen in primary tumors. Several of these genes encode pharmacologically tractable proteins, such as Syk and Ron kinases and integrin beta6, depletion of which induces epithelial-mesenchymal transformation (EMT) and apoptosis specifically in K-Ras-dependent cells. These findings indicate that epithelial differentiation and tumor cell viability are associated, and that EMT regulators in “K-Ras-addicted” cancers represent candidate therapeutic targets. K-Ras is the most frequently mutated oncogene in solid tumors and when aberrantly activated, is a potent tumor initiator. However, the identification of the critical effectors of K-Ras-mediated tumorigenesis and the development of clinically effective therapeutic strategies in this setting remain challenging. We have found that cancer cell lines harboring K-Ras mutations can be broadly classified into K-Ras-dependent and K-Ras-independent groups. By establishing a gene expression signature that can distinguish these two groups, we identified genes that are specifically up-regulated in K-Ras-dependent cells and are required for their viability. Therefore, the K-Ras dependency signature has revealed several potential therapeutic targets in a subset of otherwise pharmacologically intractable human cancers.
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影响因子：
64.8
作者：
COLLINS, S;GROUDINE, M
通讯作者：
GROUDINE, M
DOI：
10.1124/jpet.106.109058
发表时间：
2006-12-01
影响因子：
3.5
作者：
Braselmann, Sylvia;Taylor, Vanessa;Masuda, Esteban S.
通讯作者：
Masuda, Esteban S.
影响因子：
56.9
作者：
Naldini, L;Blomer, U;Trono, D
通讯作者：
Trono, D
影响因子：
50.3
作者：
Acevedo, Victor D.;Gangula, Rama D.;Spencer, David M.
通讯作者：
Spencer, David M.
影响因子：
82.9
作者：
Beer, DG;Kardia, SLR;Hanash, S
通讯作者：
Hanash, S