Division of Pulmonary Sciences and Critical Care Medicine, Department of Pathology, Colorado School of Public Health, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA.
Clin Cancer Res. 2012 Apr 15;18(8):2173-83. doi: 10.1158/1078-0432.CCR-11-2557. Epub 2012 Mar 7.
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 TGFβ type II receptor (TGFβRII) promotes lung adenocarcinoma and SCC carcinogenesis.
We examined TGFβRII expression at the protein and mRNA levels in human NSCLC samples and assessed the relationship between TGFβRII expression and clinicopathologic parameters. To determine whether sporadic TGFβRII deletion in airway epithelial cells induces NSCLC formation, we targeted TGFβRII deletion alone and in combination with oncogenic Kras(G12D) to murine airways using a keratin 5 (K5) promoter and inducible Cre recombinase.
Reduced TGFβRII 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 TGFβRII deletion in mouse airway epithelia increases the size and number of Kras(G12D)-initiated adenocarcinoma and SCC. TGFβRII deletion increases proliferation, local inflammation, and TGFβ ligand elaboration; TGFβRII knockdown in airway epithelial cells increases migration and invasion.
Reduced TGFβRII expression in human NSCLC is associated with more aggressive tumor behavior and inflammation that is, at least partially, mediated by increased TGFβ1 expression. TGFβRII deletion in mouse airway epithelial cells promotes adenocarcinoma and SCC formation, indicating that TGFβRII loss plays a causal role in lung carcinogenesis. That TGFβRII shows haploid insufficiency suggests that a 50% TGFβRII protein reduction would negatively impact lung cancer prognosis.
肺腺癌和肺鳞状细胞癌（SCC）是非小细胞肺癌（NSCLC）最常见的两种亚型。本研究旨在确定 TGFβ Ⅱ型受体（TGFβRII）表达减少是否会促进肺腺癌和 SCC 的发生。
我们检测了人 NSCLC 样本中 TGFβRII 的蛋白和 mRNA 水平，并评估了 TGFβRII 表达与临床病理参数之间的关系。为了确定气道上皮细胞中散发性 TGFβRII 缺失是否会导致 NSCLC 的形成，我们使用角蛋白 5（K5）启动子和诱导型 Cre 重组酶靶向 TGFβRII 缺失，单独或与致癌性 Kras（G12D）缺失作用于小鼠气道。
人 NSCLC 中 TGFβRII 表达减少与男性、吸烟、SCC 组织学、分化减少、肿瘤分期增加、淋巴结转移增加和生存率降低有关。在小鼠气道上皮细胞中，TGFβRII 纯合或杂合缺失会增加 Kras（G12D）引发的腺癌和 SCC 的大小和数量。TGFβRII 缺失会增加增殖、局部炎症和 TGFβ 配体的产生；气道上皮细胞中 TGFβRII 的敲低会增加迁移和侵袭。
人 NSCLC 中 TGFβRII 表达减少与更具侵袭性的肿瘤行为和炎症有关，至少部分是由 TGFβ1 表达增加介导的。在小鼠气道上皮细胞中，TGFβRII 缺失会促进腺癌和 SCC 的形成，表明 TGFβRII 缺失在肺癌发生中起因果作用。TGFβRII 表现出单倍体不足表明，TGFβRII 蛋白减少 50%会对肺癌预后产生负面影响。
