Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression
Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression
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DOI：
10.1038/sj.onc.1206817
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发表时间：
2003-10-16
期刊：
影响因子：
8
通讯作者：
Jablons, DM
中科院分区：
文献类型：
--
作者：
Uematsu, K;He, BA;Jablons, DM
非小细胞肺癌（NSCLC）是美国以及全球癌症死亡的主要原因。不幸的是，标准疗法仍然效果不佳。为了开发更有效的新疗法，需要进一步了解肺癌生物学的分子机制。在本报告中，我们表明在非小细胞肺癌中，Wnt通路通过蓬乱蛋白（Dvl）的过表达而被激活。对新鲜切除的肿瘤和肺癌细胞系的分析表明，Dvl - 3（Wnt信号传导的关键介质）过表达。具体而言，与对照配对的正常肺组织样本相比，在75%的新鲜非小细胞肺癌显微切割样本中Dvl - 3显著过表达。为了评估Wnt信号传导，特别是Dvl在肺癌中的生物学意义，我们将小干扰RNA（旨在选择性抑制人Dvl - 1、 - 2和 - 3）转染到非小细胞肺癌细胞系H1703中，已知该细胞系具有β - 连环蛋白介导的Tcf依赖性转录活性。在此，我们证明在H1703中Dvl特异性小干扰RNA处理显著降低了Dvl和β - 连环蛋白的表达，导致Tcf依赖性转录活性降低，并且重要的是，抑制了细胞生长。综上所述，这些数据支持了一个新的假说，即Dvl过表达对非小细胞肺癌中Wnt信号传导激活和细胞生长至关重要。
Non small cell lung cancer (NSCLC) is the leading cause of cancer deaths in the United States and worldwide. Unfortunately, standard therapies remain inadequate. An increased understanding of the molecular biology of lung cancer biology is required to develop more effective new therapies. In this report, we show that the Wnt pathway is activated through Dishevelled (Dvl) overexpression in NSCLC. Analysis of freshly resected tumors and lung cancer cell lines demonstrate that Dvl-3, a critical mediator of Wnt signaling, is overexpressed. Specifically, Dvl-3 was overexpressed significantly in 75% of fresh NSCLC microdissected samples compared to control paired matched normal lung samples. To evaluate the biological significance of Wnt signaling and, in particular, Dvl function in lung cancer, we transfected siRNA ( designed to inhibit selectively human Dvl-1, - 2, and - 3), to the NSCLC cell line H1703, which is known to have beta-catenin-mediated Tcf-dependent transcriptional activity. Here, we demonstrate that Dvl-specific siRNA treatment in H1703 decreases significantly Dvl and beta-catenin expression, resulting in reduction of Tcf-dependent transcriptional activity, and, importantly, growth inhibition. Taken together, these data support the novel hypothesis that Dvl overexpression is critical to Wnt signaling activation and cell growth in NSCLC.