Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer
Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer
复制标题
DOI：
10.1002/ijc.28857
复制
发表时间：
2014-11-01
影响因子：
6.4
通讯作者：
Tuereci, Oezlem
中科院分区：
文献类型：
--
作者：
Micke, Patrick;Mattsson, Johanna Sofia Margareta;Tuereci, Oezlem
紧密连接蛋白（Claudin，CLDN）是调节上皮细胞屏障功能和极性的紧密连接的中心组分。改变的CLDN表达模式已在许多癌症类型中得到证实，并且谱系特异性CLDN已被提议作为治疗靶标。本研究的目的是评估非小细胞肺癌（NSCLC）患者中表达CLDN 6和CLDN 18同种型2（CLDN18.2）的部分。通过免疫组织化学在组织微阵列上检查CLDN 6和CLDN18.2的蛋白表达（n=355），并且基于来自新鲜冷冻的NSCLC组织的基因表达微阵列数据连续地确定转录物水平（n=196）。对两者的频率、分布和与临床参数的相关性进行了分析。组织切片的免疫组织化学分析显示，在几乎不重叠的腺癌和大细胞癌亚组中，CLDN 6（6.5%）和CLDN18.2（3.7%）蛋白质呈明显的膜阳性。肺细胞和支气管上皮细胞始终呈阴性。对应于蛋白质表达，在非鳞状肺癌亚组中观察到高mRNA水平的CLDN 6（7-16%）和总CLDN 18（5-12%）。蛋白质表达与相应基因的总mRNA表达具有良好的相关性（rho=0.4-0.8）。CLDN18.2阳性肿瘤在缓慢增殖的甲状腺转录因子1（TTF-1）阴性腺癌中富集，表明同种型特异性CLDN表达可能描绘出特定的亚型。值得注意的是，在单变量[风险比（HR）：1.8; p=0.03]和多变量考克斯回归模型（HR：1.9; p=0.02）中，高CLDN 6蛋白表达与肺腺癌的较差预后相关。这些发现鼓励进一步临床探索靶向异位激活的CLDN表达作为NSCLC中有价值的治疗概念。
Claudins (CLDNs) are central components of tight junctions that regulate epithelial-cell barrier function and polarity. Altered CLDN expression patterns have been demonstrated in numerous cancer types and lineage-specific CLDNs have been proposed as therapy targets. The objective of this study was to assess which fraction of patients with non-small-cell lung cancer (NSCLC) express CLDN6 and CLDN18 isoform 2 (CLDN18.2). Protein expression of CLDN6 and CLDN18.2 was examined by immunohistochemistry on a tissue microarray (n=355) and transcript levels were supportively determined based on gene expression microarray data from fresh-frozen NSCLC tissues (n=196). Both were analyzed with regard to frequency, distribution and association with clinical parameters. Immunohistochemical analysis of tissue sections revealed distinct membranous positivity of CLDN6 (6.5%) and CLDN18.2 (3.7%) proteins in virtually non-overlapping subgroups of adenocarcinomas and large-cell carcinomas. Pneumocytes and bronchial epithelial cells were consistently negative. Corresponding to the protein expression, in subsets of non-squamous lung carcinoma high mRNA levels of CLDN6 (7-16%) and total CLDN18 (5-12%) were observed. Protein expression correlated well with total mRNA expression of the corresponding gene (rho=0.4-0.8). CLDN18.2 positive tumors were enriched among slowly proliferating, thyroid transcription factor 1 (TTF-1)-negative adenocarcinomas, suggesting that isoform-specific CLDN expression may delineate a specific subtype. Noteworthy, high CLDN6 protein expression was associated with worse prognosis in lung adenocarcinoma in the univariate [hazard ratio (HR): 1.8; p=0.03] and multivariate COX regression model (HR: 1.9; p=0.02). These findings encourage further clinical exploration of targeting ectopically activated CLDN expression as a valuable treatment concept in NSCLC.