Activation status of receptor tyrosine kinase downstream pathways in primary lung adenocarcinoma with reference of KRAS and EGFR mutations
Activation status of receptor tyrosine kinase downstream pathways in primary lung adenocarcinoma with reference of KRAS and EGFR mutations
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DOI：
10.1016/j.lungcan.2010.01.001
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发表时间：
2010-10-01
期刊：
影响因子：
5.3
通讯作者：
Ishikawa, Yuichi
中科院分区：
文献类型：
--
作者：
Hiramatsu, Miyako;Ninomiya, Hironori;Ishikawa, Yuichi
受体酪氨酸激酶信号转导通路的激活状态及其与EGFR或KRAS突变的关系已在肿瘤细胞系中得到广泛研究，但在原发肿瘤中尚不清楚。为了研究生长因子诱导信号转导通路的主要组成部分的激活状态，采用免疫组织化学方法检测了193例原发性肺腺癌手术标本中磷酸化Akt、细胞外信号调节激酶1和2(PERK)等下游蛋白的激活状态。晚期(p<；0.001)、阴性(p<；0.001)和AKT激活(p=0.015)是独立的预后不良指标。AKT激活与晚期(p=0.021)、侵袭性(p=0.004)有关，与突变无关。肿瘤转移因子-1的表达与从不吸烟(p=0.013)、侵袭前期或微侵袭(p<；0.001)和表皮生长因子受体突变(p=0.017)以及PERK(p=0.039)的表达有关。EGFR突变与PAKT和PERK的表达无相关性，这与基于培养细胞的结果不同，而KRAS突变仅与ERK激活显著相关(p=0.009)。在肺腺癌中，表达TTF-1的肿瘤在突变、信号蛋白激活和临床问题上具有明显的特征。此外，这一特性在任何肿瘤阶段的预后评估中都是重要的，而Akt的激活则根据肿瘤的不同阶段而受到异常影响，而与其细胞来源无关。不同培养细胞的信号蛋白与突变状态的关系不同。(C)2010爱思唯尔爱尔兰有限公司。保留所有权利。
The activation status of signal transduction pathways involving receptor tyrosine kinases and its association with EGFR or KRAS mutations have been widely studied using cancer cell lines, although it is still uncertain in primary tumors.To study the activation status of main components of growth factor-induced pathways, phosphorylated Akt (pAkt), extracellular signal-regulated kinases 1 and 2 (pERK) and other downstream proteins were immunohistochemically examined using surgical samples of 193 primary lung adenocarcinomas. Also, thyroid transcription factor-1 (TTF-1) expression and mutation status of EGFR and KRAS were examined.Advanced tumor stages (p < 0.001), negative TTF-1 expression (p < 0.001) and Akt activation (p = 0.015) were independent and significant poor prognostic markers. Akt activation related to advanced stage (p = 0.021), invasiveness (p = 0.004), and not to mutations. TTF-1 expression associated with never-smoker (p = 0.013), pre- or minimally invasiveness (p < 0.001) and EGFR mutations (p = 0.017) as well as with pERK (p = 0.039) expression. EGFR mutations did not correlated with pAkt and pERK expression, which was different from the results based on cultured cells, while KRAS mutations were solely and significantly linked to ERK activation (p = 0.009).In lung adenocarcinoma, tumors with TTF-1 expression have distinct characteristics regarding mutations, signal protein activation and clinical issues. Moreover, this property was revealed to be important in outcome estimation at any tumor stage, whereas Akt activation is abnormally affected according to the tumor stage regardless of their cell origin. The signal proteins were differently related to mutation status from cultured cells. (C) 2010 Elsevier Ireland Ltd. All rights reserved.