Protocadherin 17 functions as a tumor suppressor suppressing Wnt/β-catenin signaling and cell metastasis and is frequently methylated in breast cancer.
Protocadherin 17 functions as a tumor suppressor suppressing Wnt/β-catenin signaling and cell metastasis and is frequently methylated in breast cancer.
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原钙粘蛋白 17 作为肿瘤抑制剂发挥作用，抑制 Wnt/β-连环蛋白信号传导和细胞转移，并且在乳腺癌中经常被甲基化
DOI：
10.18632/oncotarget.10102
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发表时间：
2016-08-09
期刊：
影响因子：
--
通讯作者：
Tao Q
中科院分区：
文献类型：
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作者：
Yin X;Xiang T;Mu J;Mao H;Li L;Huang X;Li C;Feng Y;Luo X;Wei Y;Peng W;Ren G;Tao Q
原钙粘蛋白在细胞粘附和信号转导中起重要作用。原钙粘素的异常表达已被证明与多种肿瘤发生有关。我们以前确定PCDH 17，编码原钙粘蛋白17，作为一个频繁甲基化和下调的肿瘤抑制基因（TSG）在胃癌和结直肠癌。在这里，我们研究了PCDH 17在乳腺癌发病机制中的异常和功能。我们用PCR和免疫组化检测其在乳腺肿瘤细胞系和原发肿瘤中的表达模式。应用甲基化特异性PCR（MSP）检测其在乳腺癌细胞系和原发肿瘤中的启动子甲基化状态。使用体外和体内测定评估PCDH 17在乳腺肿瘤细胞中的生物学功能。我们发现PCDH 17在78%（7/9）的乳腺肿瘤细胞系以及89%（32/36）的原发性肿瘤中频繁下调或沉默。PCDH 17在乳腺癌中表达下调主要是由于其启动子甲基化所致。PCDH 17在乳腺癌细胞中的异位表达通过阻滞细胞周期和诱导凋亡抑制细胞增殖和迁移。在乳腺肿瘤细胞中，PCDH 17显著抑制活性β-catenin水平及其下游靶基因表达。因此，我们发现PCDH 17在乳腺癌中作为抑制Wnt/β-连环蛋白信号传导和转移的肿瘤抑制因子发挥作用，但在原发性肿瘤中经常甲基化，这可能是潜在的生物标志物。
Protocadherins play important roles in the regulation of cell adhesion and signaling transduction. Aberrant expression of protocadherins has been shown to be associated with multiple tumorigenesis. We previously identified PCDH17, encoding protocadherin 17, as a frequently methylated and downregulated tumor suppressor gene (TSG) in gastric and colorectal cancers. Here, we examined the abnormalities and functions of PCDH17 in breast cancer pathogenesis. We used PCR and immunohistochemistry to check its expression pattern in breast tumor cell lines and primary tumors. Methylation-specific PCR (MSP) was applied to examine its promoter methylation status in breast tumor cell lines and primary tumors. The biological functions of PCDH17 in breast tumor cells were assessed using in vitro and in vivo assays. We found that PCDH17 was frequently downregulated or silenced in 78% (7/9) of breast tumor cell lines, as well as 89% (32/36) of primary tumors. Downregulation of PCDH17 in breast cancer was mainly due to the methylation of its promoter. Ectopic expression of PCDH17 in breast tumor cells inhibited cell proliferation and mobility through arresting cell cycle and inducing apoptosis. In breast tumor cells, PCDH17 significantly suppressed the active β-catenin level and its downstream target gene expression. Thus, we found that PCDH17 functions as a tumor suppressor inhibiting Wnt/β-catenin signaling and metastasis in breast cancer but is frequently methylated in primary tumors which could be a potential biomarker.