Department of Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin, China.
Department of Laboratory, Aviation General Hospital, Beijing, China.
Cancer Sci. 2019 Apr;110(4):1244-1255. doi: 10.1111/cas.13935. Epub 2019 Feb 20.
Prostate cancer (PCa) death primarily occurs due to metastasis of the cells, but little is known about the underlying molecular mechanisms. This study aimed to evaluate the expression of UNC5D, a newly identified tumor suppressor gene, analyze its epigenetic alterations, and elucidate its functional relevance to PCa metastasis. Meta-analysis of publicly available microarray datasets revealed that UNC5D expression was frequently downregulated in PCa tissues and inversely associated with PCa metastasis. These results were verified in clinical specimens by real-time PCR and immunohistochemistry assays. Through methylation analysis, the downregulated expression of UNC5D in PCa tissues and cell lines was found to be attributable to the hypermethylation of the promoter. A negative correlation was observed between methylation and UNC5D mRNA expression in PCa samples. The ectopic expression of UNC5D in PCa cells effectively reduced their ability to migrate and invade both in vitro and in vivo, and siRNA-mediated knockdown of UNC5D yielded consistent results. UNC5D can recruit and activate death-associated protein kinase 1, which remained to be essential for its metastatic suppressor function. In conclusion, these results suggested that UNC5D as a novel putative metastatic suppressor gene that is commonly down-regulated by hypermethylation in PCa.
前列腺癌（PCa）的死亡主要是由于细胞转移引起的，但对于潜在的分子机制知之甚少。本研究旨在评估新鉴定的肿瘤抑制基因 UNC5D 的表达，分析其表观遗传改变，并阐明其与 PCa 转移的功能相关性。对公开可用的微阵列数据集的荟萃分析表明，UNC5D 在 PCa 组织中的表达经常下调，并且与 PCa 转移呈负相关。通过实时 PCR 和免疫组织化学检测在临床标本中验证了这些结果。通过甲基化分析，发现 PCa 组织和细胞系中 UNC5D 的下调表达归因于启动子的过度甲基化。在 PCa 样本中观察到甲基化和 UNC5D mRNA 表达之间存在负相关。UNC5D 在 PCa 细胞中的异位表达有效地降低了它们在体外和体内的迁移和侵袭能力，而 siRNA 介导的 UNC5D 敲低产生了一致的结果。UNC5D 可以招募并激活死亡相关蛋白激酶 1，这对于其转移抑制功能仍然是必不可少的。总之，这些结果表明 UNC5D 作为一种新型潜在的转移抑制基因，在 PCa 中通常通过过度甲基化而下调。
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