XEDAR as a putative colorectal tumor suppressor that mediates p53-regulated anoikis pathway
XEDAR as a putative colorectal tumor suppressor that mediates p53-regulated anoikis pathway
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DOI：
10.1038/onc.2009.154
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发表时间：
2009-08
期刊：
影响因子：
8
通讯作者：
C. Tanikawa;Y. Furukawa;N. Yoshida;H. Arakawa;Y. Nakamura;K. Matsuda
中科院分区：
文献类型：
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作者：
C. Tanikawa;Y. Furukawa;N. Yoshida;H. Arakawa;Y. Nakamura;K. Matsuda
p53基因突变的结直肠癌具有侵袭性，但其潜在机制尚未完全了解。通过筛选两个数据集的全基因组表达谱，一个为p53引入的细胞和其他的癌组织的数量，我们在这里报告X-连锁外胚层发育不良受体（XEDAR），TNFR超家族的成员，作为一种新的p53靶点，在结直肠癌的发生中具有至关重要的作用。p53通过XEDAR基因内含子1内的两个p53结合位点上调XEDAR表达。我们还发现乳腺癌和肺癌细胞系中XEDAR表达降低与p53基因突变之间存在显著相关性（分别为P= 0.0043和P= 0.0122）。此外，XEDAR基因的启动子甲基化分别在20/20个结直肠癌细胞系（100%）和6/12个结直肠癌组织（50%）中检测到。因此，在18例结直肠癌组织中的12例（66.7%）中，XEDAR表达被抑制至周围正常组织的< 25%，这是由于其表观遗传学改变和/或p53突变。我们还发现XEDAR与FAS蛋白相互作用并随后引起FAS蛋白的积累，FAS蛋白是p53诱导的TNFR的另一个成员。此外，XEDAR负调控FAK，一个核心组成部分的粘着斑。因此，XEDAR的失活导致细胞粘附和扩散的增强，以及对p53诱导的凋亡的抵抗。总之，我们的研究结果表明，XEDAR是一种假定的肿瘤抑制因子，可以通过调节细胞凋亡和失巢凋亡来防止恶性转化和肿瘤进展。
Colorectal cancers with mutations in the p53 gene have an invasive property, but its underlying mechanism is not fully understood. Through the screening of two data sets of the genome-wide expression profile, one for p53-introduced cells and the other for the numbers of cancer tissues, we report here X-linked ectodermal dysplasia receptor (XEDAR), a member of the TNFR superfamily, as a novel p53 target that has a crucial role in colorectal carcinogenesis. p53 upregulated XEDAR expression through two p53-binding sites within intron 1 of the XEDAR gene. We also found a significant correlation between decreased XEDAR expressions and p53 gene mutations in breast and lung cancer cell lines (P= 0.0043 and P= 0.0122, respectively). Furthermore, promoter hypermethylation of the XEDAR gene was detected in 20 of 20 colorectal cancer cell lines (100%) and in 6 of 12 colorectal cancer tissues (50%), respectively. Thus, the XEDAR expression was suppressed to< 25% of surrounding normal tissues in 12 of 18 colorectal cancer tissues (66.7%) due to either its epigenetic alterations and/or p53 mutations. We also found that XEDAR interacted with and subsequently caused the accumulation of FAS protein, another member of p53-inducible TNFR. Moreover, XEDAR negatively regulated FAK, a central component of focal adhesion. As a result, inactivation of XEDAR resulted in the enhancement of cell adhesion and spreading, as well as resistance to p53-induced apoptosis. Taken together, our findings showed that XEDAR is a putative tumor suppressor that could prevent malignant transformation and tumor progression by regulating apoptosis and anoikis.