PURPOSE:Abnormally high levels of epidermal growth factor receptor (EGFR) protein are associated with advanced tumor stage/grade. The objective of this study was to evaluate the effects of the specific EGFR tyrosine kinase inhibitor gefitinib on activation of the Akt and mitogen-activated protein kinase (MAPK) pathways in human urothelial cell carcinoma (UCC) cell lines and to identify potential markers of gefitinib responsiveness in biopsy samples of UCC. EXPERIMENTAL DESIGN:Changes in markers of UCC growth and invasion after exposure to gefitinib were studied in six human UCC cell lines expressing various levels of EGFR. The findings were related to activation of Akt and MAPK. We studied the influence of gefitinib on intraepithelial expansion of the responsive 1207 cell line. EGFR, Akt, and MAPK activation was studied by Western blot analysis of a panel of 57 human UCC. RESULTS:Gefitinib had a growth-inhibitory and anti-invasive effect in two of six UCC cell lines (i.e., 647V and 1207). Gefitinib was also able to block the expansion of 1207 at the expense of normal urothelial cells. These effects did not depend on the level of expression of EGFR but they were associated with the down-regulation of MAPK and Akt activity; in 1207 cells, gefitinib activity was associated with p27 up-regulation and p21 and matrix metalloproteinase-9 down-regulation. Similarly, the Akt and MAPK pathways were found to be strongly phosphorylated in association with EGFR activation in a subset of human UCC specimens. CONCLUSIONS:Activation of EGFR, Akt, and MAPK defines a subset of UCC which might provide information for the identification of gefitinib responders.

译文

目的:表皮生长因子受体(EGFR)蛋白异常高水平与晚期肿瘤分期/分级有关。这项研究的目的是评估特定的EGFR酪氨酸激酶抑制剂吉非替尼对人尿路上皮细胞癌(UCC)细胞系中Akt和丝裂原激活的蛋白激酶(MAPK)通路活化的影响,并鉴定吉非替尼的潜在标志物UCC活检样本的反应性。
实验设计:在六种表达不同水平EGFR的人UCC细胞系中研究了吉非替尼暴露后UCC生长和侵袭标志物的变化。这些发现与Akt和MAPK的激活有关。我们研究了吉非替尼对响应性1207细胞系上皮内扩增的影响。 EGFR,Akt和MAPK活化是通过对57个人的UCC进行蛋白质印迹分析来研究的。
结果:吉非替尼在六个UCC细胞系中的两个(即647V和1207)具有生长抑制和抗侵袭作用。吉非替尼还能够以正常尿路上皮细胞为代价来阻止1207的扩增。这些作用并不取决于EGFR的表达水平,但与MAPK和Akt活性的下调有关。在1207个细胞中,吉非替尼的活性与p27的上调以及p21和基质金属蛋白酶9的下调有关。同样,在人类UCC标本的一个子集中,发现Akt和MAPK途径与EGFR激活相关地被强烈磷酸化。
结论:EGFR,Akt和MAPK的激活定义了UCC的一个子集,该子集可能为鉴定吉非替尼反应者提供信息。

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