Desmoplakin acts as a tumor suppressor by inhibition of the Wnt/β-catenin signaling pathway in human lung cancer
Desmoplakin acts as a tumor suppressor by inhibition of the Wnt/β-catenin signaling pathway in human lung cancer
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DOI：
10.1093/carcin/bgs226
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发表时间：
2012-10-01
期刊：
影响因子：
4.7
通讯作者：
Petersen, Iver
中科院分区：
文献类型：
--
作者：
Yang, Linlin;Chen, Yuan;Petersen, Iver
桥粒是细胞间的连接点，它赋予细胞强大的粘附力，从而赋予上皮组织抵抗机械应力的能力。大量证据表明桥粒蛋白表达的降低与各种癌症的不良预后相关。桥粒斑蛋白（DSP）作为桥粒斑蛋白的重要组成部分，其在肿瘤中的功能作用尚不清楚。在这里，我们报告了DSP在非小细胞肺癌（NSCLC）中的抗致瘤活性。我们通过DSP DNA甲基化发现，DSP表达在11个肺癌细胞系中的8个和56个原发性肺肿瘤中的34个中下调。DSP在NSCLC细胞系H157中的异位表达显著抑制细胞增殖、锚定非依赖性生长、迁移和侵袭，并且还增加NSCLC细胞对抗癌药物吉西他滨诱导的凋亡的敏感性。此外，DSP的过表达增强斑珠蛋白（-连环蛋白）的表达，导致T细胞因子/淋巴增强因子（TCF/LEF）依赖的转录活性降低，Wnt/-连环蛋白靶基因Axin 2和基质金属蛋白酶MMP 14的表达降低。根据，DSP抑制小干扰RNA导致下调斑珠蛋白和上调-连环蛋白和MMP 14。综上所述，这些数据表明DSP在肺癌中通过表观遗传机制失活，增加对抗癌药物诱导的细胞凋亡的敏感性，并具有肿瘤抑制功能，可能通过抑制NSCLC细胞中的Wnt/β-连环蛋白信号通路。DSP的表观遗传调节及其增加抗癌药物诱导的细胞凋亡的敏感性的能力具有潜在的临床应用意义。
Desmosomes are intercellular junctions that confer strong cellcell adhesion, thus conferring resistance against mechanical stress on epithelial tissues. A body of evidence indicates that decreased expression of desmosomal proteins is associated with poor prognosis in various cancers. As a key component of desmosomal plaque proteins, the functional role of desmoplakin (DSP) in cancer is not yet elucidated. Here, we reported the anti-tumorigenic activity of DSP in non-small cell lung cancer (NSCLC). We found by DSP DNA methylation that DSP expression was downregulated in 8 out of 11 lung cancer cell lines and in 34 out of 56 primary lung tumors . Ectopic expression of DSP in the NSCLC cell line H157 significantly inhibited cell proliferation, anchorage-independent growth, migration and invasion and also increased the sensitivity of NSCLC cells to apoptosis induced by an anticancer drug, gemcitabine. Furthermore, overexpression of DSP enhanced expression of plakoglobin (-catenin), resulting in decreased T-cell factor/lymphoid enhancer factor (TCF/LEF)-dependent transcriptional activity and reduced expression of the Wnt/-catenin target genes Axin2 and matrix metalloproteinase MMP14. In accordance, DSP suppression by small interfering RNA resulted in downregulation of plakoglobin and upregulation of -catenin and MMP14. Taken together, these data suggest that DSP is inactivated in lung cancer by an epigenetic mechanism, increases the sensitivity to anticancer drug-induced apoptosis and has tumor-suppressive function, possibly through inhibition of the Wnt/-catenin signaling pathway in NSCLC cells. The epigenetic regulation of DSP and its ability to increase the sensitivity to anticancer drug-induced apoptosis has potential implications for clinical application.