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首页> 外文期刊>Cellular Signalling >Oncogenic K-Ras down-regulates Rac1 and RhoA activity and enhances migration and invasion of pancreatic carcinoma cells through activation of p38
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Oncogenic K-Ras down-regulates Rac1 and RhoA activity and enhances migration and invasion of pancreatic carcinoma cells through activation of p38

机译：致癌性K-Ras通过激活p38下调Rac1和RhoA活性并增强胰腺癌细胞的迁移和侵袭

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摘要

Activating mutations in the K-ras gene are genetic alterations frequently found in human carcinomas, particularly in pancreatic adenocarcinomas. Mutation of the K-ras gene is thought to be an early and important event in pancreatic tumor initiation, but the precise role of the mutant K-Ras proteins in neoplastic progression is still unknown. In the present study, we have characterized the influence of oncogenic K-Ras on the phenotype and on the signal transduction of epitheloid PANC-1 pancreatic carcinoma cells by generating PANC-1 cell clones, which stably express EGFP(enhanced green fluorescent protein)-K-Ras (V12). EGFP-K-Ras (V12)-expressing cells exhibited a more fibroblastoid cellular phenotype with irregular cell shape and disorganized cytokeratin filaments. Moreover, these cells showed a marked enhancement of their migratory and invasive properties. Stable expression of EGFP-K-Ras (V12) down-regulated the activity of Rac1 and RhoA, resulting in reduced subcortical actin filaments and stress fibers, which might contribute to the epithelial dedifferentiation. Characterization of the activity of mitogen-activated protein kinases revealed that EGFP-K-Ras (V12) enhanced the activity of p38, but did not affect the activities of the Raf/MEK/ERK cascade and JNK. While inhibition of either MEK or JNK activity had no effect on EGFP-K-Ras (V12)-induced migration, inhibition of p38 activity markedly reduced EGFP-K-Ras (V12)-induced migration. Collectively, the results suggest that oncogenic K-Ras enhances the malignant phenotype and identify the mitogen-activated protein kinase p38 as a target to inhibit oncogenic K-Ras-induced pancreatic tumor cell migration. (c) 2005 Elsevier Inc. All rights reserved.
机译：K-ras基因中的活化突变是在人类癌症中，特别是在胰腺腺癌中经常发现的遗传改变。 K-ras基因的突变被认为是胰腺肿瘤发生的早期和重要事件，但突变K-Ras蛋白在肿瘤进展中的确切作用仍然未知。在本研究中，我们通过产生稳定表达EGFP（增强型绿色荧光蛋白）的PANC-1细胞克隆，表征了致癌性K-Ras对表型和上皮PANC-1胰腺癌细胞信号转导的影响。 K-Ras（V12）。表达EGFP-K-Ras（V12）的细胞表现出更多的成纤维细胞表型，具有不规则的细胞形状和紊乱的细胞角蛋白丝。而且，这些细胞显示出其迁移和侵袭特性的显着增强。 EGFP-K-Ras（V12）的稳定表达下调了Rac1和RhoA的活性，导致皮层下肌动蛋白丝和应力纤维减少，这可能有助于上皮去分化。丝裂原活化蛋白激酶活性的表征表明，EGFP-K-Ras（V12）增强了p38的活性，但不影响Raf / MEK / ERK级联和JNK的活性。虽然抑制MEK或JNK活性对EGFP-K-Ras（V12）诱导的迁移没有影响，但抑制p38活性显着降低了EGFP-K-Ras（V12）诱导的迁移。总体而言，结果表明致癌性K-Ras增强了恶性表型，并鉴定了促分裂原活化的蛋白激酶p38作为抑制致癌性K-Ras诱导的胰腺肿瘤细胞迁移的靶标。 （c）2005 Elsevier Inc.保留所有权利。

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