Epigenetic Changes in Basal Cell Carcinoma Affect SHH and WNT Signaling Components
Epigenetic Changes in Basal Cell Carcinoma Affect SHH and WNT Signaling Components
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DOI：
10.1371/journal.pone.0051710
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发表时间：
2012-12-17
期刊：
影响因子：
3.7
通讯作者：
van Steensel, Maurice A. M.
中科院分区：
文献类型：
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作者：
Brinkhuizen, Tjinta;van den Hurk, Karin;van Steensel, Maurice A. M.
背景资料：基底细胞癌（BCC）的遗传背景已被广泛研究，而其表观遗传组成受到的关注相对较少。表观遗传学改变，如启动子超甲基化沉默肿瘤抑制基因（TSG）在几种恶性肿瘤。与Sonic Hedgehog（SHH）、WNT信号传导和通过甲基化特异性PCR检测112个BCC和124个健康对照样本的大系列（毛囊）肿瘤。与正常皮肤相比，BCC中SHH（P = 0.016）、腺瘤性结肠息肉病（APC）（P = 0.003）、分泌型卷曲相关蛋白5（SFRP 5）（P = 0.004）和Ras相关结构域家族1A（RASSF 1A）（P = 0.023）的基因启动子显示出显著更多的甲基化。与正常皮肤（n = 6）相比，BCC（n = 6）中APC和SFRP 5的这四个基因的mRNA水平降低。免疫组化染色显示SHH、APC和RASSF 1A在蛋白水平表达下调（P < 0.001）。通过β-连环蛋白染色可见典型WNT活性增加，仅在28/101（27.7%）的BCC中显示核β-连环蛋白。核β-连环蛋白在一些样品中的缺失可能是由于高水平的膜E-钙粘蛋白（在94.1%的样品）。结论：我们提供的证据表明，启动子超甲基化的关键球员内SHH和WNT途径是频繁的BCC，符合他们已知的组成性激活BCC。表观遗传基因沉默促进BCC肿瘤发生，为治疗提供了新途径。
Background: The genetic background of Basal Cell Carcinoma (BCC) has been studied extensively, while its epigenetic makeup has received comparatively little attention. Epigenetic alterations such as promoter hypermethylation silence tumor suppressor genes (TSG) in several malignancies.Objective: We sought to analyze the promoter methylation status of ten putative (tumor suppressor) genes that are associated with Sonic Hedgehog (SHH), WNT signaling and (hair follicle) tumors in a large series of 112 BCC and 124 healthy control samples by methylation-specific PCR.Results: Gene promoters of SHH (P = 0.016), adenomatous polyposis coli (APC) (P = 0.003), secreted frizzled-related protein 5 (SFRP5) (P = 0.004) and Ras association domain family 1A (RASSF1A) (P = 0.023) showed significantly more methylation in BCC versus normal skin. mRNA levels of these four genes were reduced for APC and SFRP5 in BCC (n = 6) vs normal skin (n = 6). Down regulation of SHH, APC and RASSF1A could be confirmed on protein level as well (P < 0.001 for all genes) by immunohistochemical staining. Increased canonical WNT activity was visualized by beta-catenin staining, showing nuclear beta-catenin in only 28/101 (27.7%) of BCC. Absence of nuclear beta-catenin in some samples may be due to high levels of membranous E-cadherin (in 94.1% of the samples).Conclusions: We provide evidence that promoter hypermethylation of key players within the SHH and WNT pathways is frequent in BCC, consistent with their known constitutive activation in BCC. Epigenetic gene silencing putatively contributes to BCC tumorigenesis, indicating new venues for treatment.