CLDN8, an androgen-regulated gene, promotes prostate cancer cell proliferation and migration.
CLDN8, an androgen-regulated gene, promotes prostate cancer cell proliferation and migration.
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DOI：
10.1111/cas.13269
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发表时间：
2017-07
期刊：
影响因子：
5.7
通讯作者：
Inoue S
中科院分区：
文献类型：
--
作者：
Ashikari D;Takayama KI;Obinata D;Takahashi S;Inoue S
前列腺癌细胞的增殖受雄激素受体（AR）信号通路控制。然而，AR靶基因的功能尚未完全阐明。在以前的研究中，我们已经确定了前列腺癌细胞中的全局AR结合位点和AR靶基因。在这里，我们专注于Claudin 8（CLDN8），一种构成细胞膜紧密连接的蛋白质。我们在启动子区发现了一个AR结合位点，并在序列中发现了两个功能性雄激素反应元件。报告基因测定显示，雄激素对CLDN8启动子的转录激活依赖于这些雄激素响应元件。此外，CLDN8 mRNA被雄激素时间依赖性地诱导，并且该诱导被AR抑制剂阻断，表明AR参与转录激活。此外，我们通过CLDN8 mRNA的过表达和敲低进行的功能分析表明，CLDN8促进前列腺癌细胞增殖和迁移。与良性组织相比，紧密连接蛋白8在前列腺癌临床样品中过表达。此外，我们发现CLDN8调节细胞内信号转导并稳定细胞骨架。综上所述，这些结果表明CLDN8作为AR下游信号起作用以促进前列腺癌的进展。Claudin 8可能成为前列腺癌治疗的一个新的分子靶点。
The proliferation of prostate cancer cells is controlled by the androgen receptor (AR) signaling pathway. However, the function of AR target genes has not been fully elucidated. In previous studies, we have identified global AR binding sites and AR target genes in prostate cancer cells. Here, we focused on Claudin 8 (CLDN8), a protein constituting tight junctions in cell membranes. We found one AR binding site in the promoter region and two functional androgen‐responsive elements in the sequence. Reporter assay revealed that transcriptional activation of the CLDN8 promoter by androgen is dependent on these androgen‐responsive elements. Furthermore, CLDN8 mRNA is induced by androgen time‐dependently and the induction is blocked by AR inhibitor, suggesting that AR is involved in the transcriptional activation. In addition, our functional analyses by overexpression and knockdown of CLDN8 mRNA indicate that CLDN8 promotes prostate cancer cell proliferation and migration. Claudin 8 was overexpressed in prostate cancer clinical samples compared to benign tissues. Furthermore, we found that CLDN8 regulates intracellular signal transduction and stabilizes the cytoskeleton. Taken together, these results indicate that CLDN8 functions as an AR downstream signal to facilitate the progression of prostate cancer. Claudin 8 may be a novel molecular target for prostate cancer therapy.