Paxillin is a target for somatic mutations in lung cancer: Implications for cell growth and invasion
Paxillin is a target for somatic mutations in lung cancer: Implications for cell growth and invasion
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DOI：
10.1158/0008-5472.can-07-1998
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发表时间：
2008-01-01
期刊：
影响因子：
11.2
通讯作者：
Salgia, Ravi
中科院分区：
文献类型：
--
作者：
Jagadeeswaran, Ramasamy;Surawska, Hanna;Salgia, Ravi
肺癌的特征是细胞的异常生长和侵袭，而肌动蛋白细胞骨架在这些过程中起着重要作用。粘着斑蛋白桩蛋白是参与关键信号转导的许多癌基因的靶标，并且在细胞运动和迁移中很重要。在肺癌组织中，我们发现桩蛋白高表达（与正常肺相比），扩增（12.1%，66例中的8例），并与MET和表皮生长因子受体（EGFR）基因拷贝数增加相关，或突变（体细胞突变率为9.4%，IS为191）。桩蛋白突变（21个中的19个）聚集在LD基序I和2与LIM结构域之间。最常见的点突变（A127 T）增强肺癌细胞的生长，集落形成，粘着斑形成，并与Bcl-2在体外共定位。来自突变桩蛋白的RNA干扰的基因沉默导致细胞活力降低。A127 T桩蛋白的小鼠体内异种移植模型显示肿瘤生长、细胞增殖和侵袭增加。这些结果确立了桩蛋白在肺癌中的重要作用。
Lung cancer is characterized by abnormal cell growth and invasion, and the actin cytoskeleton plays a major role in these processes. The focal adhesion protein paxillin is a target of a number of oncogenes involved in key signal transduction and important in cell motility and migration. In lung cancer tissues, we have found that paxillin was highly expressed (compared with normal lung), amplified (12.1%, 8 of 66) and correlated with increased MET and epidermal growth factor receptor (EGFR) gene copy numbers, or mutated (somatic mutation rate of 9.4%, IS of 191). Paxillin mutations (19 of 21) were clustered between LD motifs I and 2 and the LIM domains. The most frequent point mutation (A127T) enhanced lung cancer cell growth, colony formation, focal adhesion formation, and colocalized with Bcl-2 in vitro. Gene silencing from RNA interference of mutant paxillin led to reduction of cell viability. A murine in vivo xenograft model of A127T paxillin showed an increase in tumor growth, cell proliferation, and invasion. These results establish an important role for paxillin in lung cancer.