Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells
Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells
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DOI：
10.1038/sj.onc.1202957
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发表时间：
1999-10-07
期刊：
影响因子：
8
通讯作者：
Frame, MC
中科院分区：
文献类型：
--
作者：
Agochiya, M;Brunton, VG;Frame, MC
粘着斑激酶（pp 125（FAK））存在于细胞/细胞外基质粘附的位点，并与细胞行为的控制有关。特别是，作为整合素刺激的信号转导途径的关键组分，pp 125（FAK）参与细胞过程，如扩散、运动、生长和存活。此外，许多报告表明，pp 125（FAK）可能在不同来源的人类肿瘤细胞中上调，因此，pp 125（FAK）在侵袭性癌症的发展中的作用已被提出。然而，迄今为止，导致肿瘤细胞中pp 125（FAK）表达升高的机制尚未确定。本文采用原位杂交技术证实了人fak基因位于染色体8 q上，并报道了在所有病例中，侵袭性鳞状细胞癌细胞系中pp 125（FAK）蛋白的升高伴随着fak基因拷贝数的增加。此外，我们还观察到鳞状细胞癌冰冻切片中fak拷贝数的增加。此外，在许多来源于人肺、乳腺和结肠肿瘤的细胞系中也观察到fak基因的剂量增加，包括其中fak扩增的两个细胞系Calu 3和HT 29。此外，在人结肠癌进展的体外模型中，在从腺瘤转化为癌的过程中，fak基因的拷贝数增加，这与pp 125（FAK）蛋白表达的增加有关。因此，我们首次表明，来源于侵袭性上皮肿瘤的许多细胞系具有增加剂量的fak基因，这可能有助于通常观察到的蛋白表达的升高。尽管fak位点附近的其他基因被共同扩增或拷贝数增加，包括原癌基因c-myc，pp 125（FAK）在控制肿瘤细胞的生长、存活和侵袭性方面的生物学特性表明，它可能有助于维持编码这些基因的染色体8 q区域的增加剂量的选择压力。
Focal adhesion kinase (pp125(FAK)) is present at sites of cell/extracellular matrix adhesion and has been implicated in the control of cell behaviour. In particular, as a key component of integrin-stimulated signal transduction pathways, pp125(FAK) is involved in cellular processes such as spreading, motility, growth and survival. In addition, a number of reports have indicated that pp125(FAK) may be up-regulated in human tumour cells of diverse origin, and consequently, a role has been proposed for pp125(FAK) in the development of invasive cancers. However, to date the mechanisms that lead to elevated pp125(FAK) expression in tumour cells have not been determined. Here ne used iii situ hybridization to confirm chromosome 8q as the genomic location of the human fak gene and report that elevation of pp125(FAK) protein in cell lines derived from invasive squamous cell carcinomas is accompanied by gains in copy number of the fak gene in all cases examined, In addition,,ve observed increased fak copy number in frozen sections of squamous cell carcinomas. Furthermore, increased dosage of the fak gene was also observed in many cell lines derived from human tumours of lung, breast and colon, including two cell lines Calu3 and HT29, in which fak was amplified. In addition, in an in vitro model for human colon cancer progression there was a copy number gain of the fak gene during conversion from adenoma to carcinoma, which was associated with increased pp125(FAK) protein expression, Thus, ne show for the first time that many cell lines derived from invasive epithelial tumours hare increased dosage of the fak gene, which may contribute to the elevated protein expression commonly observed, Although other genes near the fak locus are coamplified or increased in copy number, including the proto-oncogene c-myc, the biological properties of pp125(FAK) in controlling the growth, survival and invasiveness of tumour cells, suggest that it may contribute to the selection pressure for maintaining increased dosage of the region of chromosome 8q that encodes these genes.