Loss of Transforming Growth Factor Beta Type II Receptor Increases Aggressive Tumor Behavior and Reduces Survival in Lung Adenocarcinoma and Squamous Cell Carcinoma
Loss of Transforming Growth Factor Beta Type II Receptor Increases Aggressive Tumor Behavior and Reduces Survival in Lung Adenocarcinoma and Squamous Cell Carcinoma
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DOI：
10.1158/1078-0432.ccr-11-2557
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发表时间：
2012-04-15
影响因子：
11.5
通讯作者：
Wang, Xiao-Jing
中科院分区：
文献类型：
--
作者：
Malkoski, Stephen P.;Haeger, Sarah M.;Wang, Xiao-Jing
目的：肺腺癌和肺鳞癌是非小细胞肺癌最常见的亚型。本研究的目的是确定是否减少表达的TGF β II型受体（TGF β RII）促进肺腺癌和SCC cancerogenicity.Experimental设计：我们研究了TGF β RII的表达在蛋白质和mRNA水平在人类非小细胞肺癌样本和评估TGF β RII的表达和临床病理参数之间的关系。为了确定气道上皮细胞中的散发性TGF β RII缺失是否诱导NSCLC形成，我们使用角蛋白5（K5）启动子和诱导型Cre重组酶将单独的TGF β RII缺失和与致癌Kras（G12 D）组合靶向小鼠气道。人NSCLC中TGF β RII表达降低与男性、吸烟、SCC组织学、分化降低、肿瘤分期增加增加淋巴结转移和降低生存率。小鼠气道上皮中TGF β RII纯合或杂合缺失增加Kras（G12 D）起始腺癌和SCC的大小和数量TGF β RII缺失增加增殖，局部炎症和TGF β配体的制定; TGF β RII敲低气道上皮细胞增加迁移和invasion.Conclusions：减少TGF β RII表达在人类NSCLC与更积极的肿瘤行为和炎症，至少部分，介导的TGF β 1表达增加。小鼠气道上皮细胞中TGF β RII缺失促进腺癌和SCC形成，表明TGF β RII缺失在肺癌发生中起因果作用。TGF β RII显示单倍体不足表明TGF β RII蛋白减少50%将对肺癌预后产生负面影响。临床癌症研究; 18（8）; 2173-83。(C)2012年AACR。
Purpose: Lung adenocarcinoma and lung squamous cell carcinoma (SCC) are the most common non-small cell lung cancer (NSCLC) subtypes. This study was designed to determine whether reduced expression of TGF beta type II receptor (TGF beta RII) promotes lung adenocarcinoma and SCC carcinogenesis.Experimental Design: We examined TGF beta RII expression at the protein and mRNA levels in human NSCLC samples and assessed the relationship between TGF beta RII expression and clinicopathologic parameters. To determine whether sporadic TGF beta RII deletion in airway epithelial cells induces NSCLC formation, we targeted TGF beta RII deletion alone and in combination with oncogenic Kras(G12D) to murine airways using a keratin 5 (K5) promoter and inducible Cre recombinase.Results: Reduced TGF beta RII expression in human NSCLC is associated with male gender, smoking, SCC histology, reduced differentiation, increased tumor stage, increased nodal metastasis, and reduced survival. Homozygous or heterozygous TGF beta RII deletion in mouse airway epithelia increases the size and number of Kras(G12D)-initiated adenocarcinoma and SCC. TGF beta RII deletion increases proliferation, local inflammation, and TGF beta ligand elaboration; TGF beta RII knockdown in airway epithelial cells increases migration and invasion.Conclusions: Reduced TGF beta RII expression in human NSCLC is associated with more aggressive tumor behavior and inflammation that is, at least partially, mediated by increased TGF beta 1 expression. TGF beta RII deletion in mouse airway epithelial cells promotes adenocarcinoma and SCC formation, indicating that TGF beta RII loss plays a causal role in lung carcinogenesis. That TGF beta RII shows haploid insufficiency suggests that a 50% TGF beta RII protein reduction would negatively impact lung cancer prognosis. Clin Cancer Res; 18(8); 2173-83. (C) 2012 AACR.