Identification of a subset of human non-small cell lung cancer patients with high PI3Kβ and low PTEN expression, more prevalent in squamous cell carcinoma.
Identification of a subset of human non-small cell lung cancer patients with high PI3Kβ and low PTEN expression, more prevalent in squamous cell carcinoma.
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DOI：
10.1158/1078-0432.ccr-13-1638
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发表时间：
2014-02-01
期刊：
影响因子：
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通讯作者：
Womack C
中科院分区：
文献类型：
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作者：
Cumberbatch M;Tang X;Beran G;Eckersley S;Wang X;Ellston RP;Dearden S;Cosulich S;Smith PD;Behrens C;Kim ES;Su X;Fan S;Gray N;Blowers DP;Wistuba II;Womack C
磷脂酰肌醇3-激酶(PI3K)通路是一条重要的致癌信号通路，也是治疗干预的重要靶点。通过PI3K途径的信号受肿瘤抑制基因PTEN的调节，PTEN在许多人类癌症中是缺失或突变的。PI3K信号网络在肺癌中的分子特征尚不清楚，尤其是PI3KPTEN在非小细胞肺癌中的作用及其与β的关系尚不清楚。针对PI3KPTEN和β的抗体被证实，并用免疫组织化学方法检测了240例非小细胞肺癌切除组织中的表达。初步观察扩展到一组独立的组织(TMA组2)，包括在单独实验室使用相同验证的抗体和染色方案进行分析的820名非小细胞肺癌患者样本。研究PI3K、β和PTEN的染色强度，并将这些标记在单个肿瘤核心的共存情况进行相关性分析。PI3Kβ在鳞癌中的表达明显高于腺癌。相反，鳞癌组织中PTEN缺失的程度大于腺癌。对单个患者样本的详细相关性分析显示，与腺癌相比，鳞癌的比例明显增加，PI3Kβ的表达较高，而PTEN的表达较低。在对TMA SET 2进行独立分析后，这些发现得到了加强。我们首次发现了非小细胞肺癌的一个亚群，在鳞癌中更普遍，PI3Kβ的表达增加伴随着PTEN的减少/缺失，对这些人来说，选择性PI3Kβ抑制剂可能会获得更大的临床益处。
The phosphoinositide 3-kinase (PI3K) pathway is a major oncogenic signaling pathway and an attractive target for therapeutic intervention. Signaling through the PI3K pathway is moderated by the tumor suppressor PTEN, which is deficient or mutated in many human cancers. Molecular characterization of the PI3K signaling network has not been well defined in lung cancer; in particular, the role of PI3Kβ and its relation to PTEN in non–small cell lung cancer NSCLC remain unclear. Antibodies directed against PI3Kβ and PTEN were validated and used to examine, by immunohistochemistry, expression in 240 NSCLC resection tissues [tissue microarray (TMA) set 1]. Preliminary observations were extended to an independent set of tissues (TMA set 2) comprising 820 NSCLC patient samples analyzed in a separate laboratory applying the same validated antibodies and staining protocols. The staining intensities for PI3Kβ and PTEN were explored and colocalization of these markers in individual tumor cores were correlated. PI3Kβ expression was elevated significantly in squamous cell carcinomas (SCC) compared with adenocarcinomas. In contrast, PTEN loss was greater in SCC than in adenocarcinoma. Detailed correlative analyses of individual patient samples revealed a significantly greater proportion of SCC in TMA set 1 with higher PI3Kβ and lower PTEN expression when compared with adenocarcinoma. These findings were reinforced following independent analyses of TMA set 2. We identify for the first time a subset of NSCLC more prevalent in SCC, with elevated expression of PI3Kβ accompanied by a reduction/loss of PTEN, for whom selective PI3Kβ inhibitors may be predicted to achieve greater clinical benefit.