Jagadeeswaran Ramasamy, Surawska Hanna, Krishnaswamy Soundararajan, Janamanchi Varalakshmi, Mackinnon A Craig, Seiwert Tanguy Y, Loganathan Sivakumar, Kanteti Rajani, Reichman Trevor, Nallasura Vidya, Schwartz Stuart, Faoro Leonardo, Wang Yi-Ching, Girard Luc, Tretiakova Maria S, Ahmed Salman, Zumba Osvaldo, Soulii Lioubov, Bindokas Vytas P, Szeto Livia L, Gordon Gavin J, Bueno Raphael, Sugarbaker David, Lingen Mark W, Sattler Martin, Krausz Thomas, Vigneswaran Wickii, Natarajan Viswanathan, Minna John, Vokes Everett E, Ferguson Mark K, Husain Aliya N, Salgia Ravi
Department of Medicine, University of Chicago Cancer Research Center, University of Chicago Medical Center, Pritzker School of Medicine, Chicago, Illinois 60637, USA.
Cancer Res. 2008 Jan 1;68(1):132-42. doi: 10.1158/0008-5472.CAN-07-1998.
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%, 18 of 191). Paxillin mutations (19 of 21) were clustered between LD motifs 1 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.
肺癌的特征是细胞异常生长和侵袭，而肌动蛋白细胞骨架在这些过程中起主要作用。粘着斑蛋白桩蛋白是许多参与关键信号转导的癌基因的靶点，在细胞运动和迁移中起重要作用。在肺癌组织中，我们发现桩蛋白高表达（与正常肺组织相比）、扩增（12.1%，66例中有8例），并与MET和表皮生长因子受体（EGFR）基因拷贝数增加相关，或发生突变（体细胞突变率为9.4%，191例中有18例）。桩蛋白突变（21例中有19例）集中在LD基序1和2与LIM结构域之间。最常见的点突变（A127T）在体外增强了肺癌细胞的生长、集落形成、粘着斑形成，并与Bcl-2共定位。通过RNA干扰对突变型桩蛋白进行基因沉默导致细胞活力降低。A127T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。
