RNA Interference Against Cancer/Testis Genes Identifies Dual Specificity Phosphatase 21 as a Potential Therapeutic Target in Human Hepatocellular Carcinoma
RNA Interference Against Cancer/Testis Genes Identifies Dual Specificity Phosphatase 21 as a Potential Therapeutic Target in Human Hepatocellular Carcinoma
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针对癌症/睾丸基因的 RNA 干扰将双特异性磷酸酶 21 确定为人类肝细胞癌的潜在治疗靶点
DOI：
10.1002/hep.26665
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发表时间：
2014-02-01
期刊：
影响因子：
13.5
通讯作者：
Han, Ze-Guang
中科院分区：
文献类型：
--
作者：
Deng, Qing;Li, Kun-Yu;Han, Ze-Guang
癌症/睾丸（CT）抗原已被认为是治疗癌症的治疗靶标。然而，一个中心问题是它们的表达是否有助于肿瘤发生，或者它们是否是来自细胞转化过程的功能无关的副产物。在任何情况下，这些CT抗原对于癌细胞存活是必需的，并且可以作为潜在的治疗靶点。最近，基于细胞的RNA干扰（RNAi）筛选已被证明是一个强大的方法来确定潜在的治疗靶点。在这项研究中，我们试图确定新的CT抗原作为人类肝细胞癌（HCC）的潜在治疗靶点，并通过基因表达谱的生物信息学分析筛选X染色体上的179个潜在CT基因。然后针对这些潜在的CT基因进行RNAi筛选，确定了维持Focus和PLC/PRF/5细胞存活所需的9个基因。在这9个基因中，生理睾丸限制性双特异性磷酸酶21（DUSP 21）编码的双特异性磷酸酶在118例人HCC标本中有39例（33%）上调。异位DUSP 21对肝癌细胞的增殖和集落形成无明显影响。然而，DUSP 21沉默显著抑制HCC细胞的细胞增殖、集落形成和体内致瘤性。针对内源性DUSP 21的腺病毒介导的RNAi和去端胶原/siRNA混合物的施用显著抑制了小鼠中的异种移植HCC肿瘤。进一步的研究表明，DUSP 21基因敲低导致细胞周期停滞于G（1）期，细胞衰老，以及一些在细胞周期和/或衰老中起作用的因子的表达变化。此外，DUSP 21敲低的抗增殖作用是通过激活HCC中的p38丝裂原活化蛋白激酶。结论：DUSP 21在维持肝癌细胞增殖中起重要作用，因此可能作为肝癌治疗的潜在靶点。（肝病学2014;59：518-530）
Cancer/testis (CT) antigens have been considered therapeutic targets for treating cancers. However, a central question is whether their expression contributes to tumorigenesis or if they are functionally irrelevant by-products derived from the process of cellular transformation. In any case, these CT antigens are essential for cancer cell survival and may serve as potential therapeutic targets. Recently, the cell-based RNA interference (RNAi) screen has proven to be a powerful approach for identifying potential therapeutic targets. In this study we sought to identify new CT antigens as potential therapeutic targets for human hepatocellular carcinoma (HCC), and 179 potential CT genes on the X chromosome were screened through a bioinformatics analysis of gene expression profiles. Then an RNAi screen against these potential CT genes identified nine that were required for sustaining the survival of Focus and PLC/PRF/5 cells. Among the nine genes, the physiologically testis-restricted dual specificity phosphatase 21 (DUSP21) encoding a dual specificity phosphatase was up-regulated in 39 (33%) of 118 human HCC specimens. Ectopic DUSP21 had no obvious impact on proliferation and colony formation in HCC cells. However, DUSP21 silencing significantly suppressed cell proliferation, colony formation, and in vivo tumorigenicity in HCC cells. The administration of adenovirus-mediated RNAi and an atelocollagen/siRNA mixture against endogenous DUSP21 significantly suppressed xenograft HCC tumors in mice. Further investigations showed that DUSP21 knockdown led to arrest of the cell cycle in G(1) phase, cell senescence, and expression changes of some factors with functions in the cell cycle and/or senescence. Furthermore, the antiproliferative role of DUSP21 knockdown is through activation of p38 mitogen-activated protein kinase in HCC. Conclusion: DUSP21 plays an important role in sustaining HCC cell proliferation and may thus act as a potential therapeutic target in HCC treatment. (Hepatology 2014;59:518-530)