Key Laboratory of Systems Biomedicine (Ministry of Education) of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
Hepatology. 2014 Feb;59(2):518-30. doi: 10.1002/hep.26665. Epub 2013 Dec 18.
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 G1 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.
DUSP21 plays an important role in sustaining HCC cell proliferation and may thus act as a potential therapeutic target in HCC treatment.
癌症/睾丸（CT）抗原被认为是治疗癌症的治疗靶点。然而，一个核心问题是它们的表达是否有助于肿瘤发生，或者它们是否是细胞转化过程中功能上无关的副产品。在任何情况下，这些 CT 抗原对于癌细胞的存活都是必不可少的，并且可能是潜在的治疗靶点。最近，基于细胞的 RNA 干扰（RNAi）筛选已被证明是一种识别潜在治疗靶点的强大方法。在这项研究中，我们试图鉴定新的 CT 抗原作为人类肝细胞癌（HCC）的潜在治疗靶点，并通过对基因表达谱的生物信息学分析筛选出 X 染色体上的 179 个潜在 CT 基因。然后，针对这些潜在 CT 基因的 RNAi 筛选鉴定出了维持 Focus 和 PLC/PRF/5 细胞存活所需的 9 个基因。在这 9 个基因中，生理上局限于睾丸的双特异性磷酸酶 21（DUSP21）编码一种双特异性磷酸酶，在 118 个人 HCC 标本中的 39 个（33%）中上调。外源性 DUSP21 对 HCC 细胞的增殖和集落形成没有明显影响。然而，DUSP21 沉默显著抑制 HCC 细胞的增殖、集落形成和体内致瘤性。腺病毒介导的 RNAi 和针对内源性 DUSP21 的胶原/siRNA 混合物的给药显著抑制了小鼠异种移植 HCC 肿瘤。进一步的研究表明，DUSP21 敲低导致细胞周期停滞在 G1 期，细胞衰老，以及一些具有细胞周期和/或衰老功能的因子的表达变化。此外，DUSP21 敲低的抗增殖作用是通过 HCC 中 p38 丝裂原活化蛋白激酶的激活。
DUSP21 在维持 HCC 细胞增殖中起重要作用，因此可能是 HCC 治疗中的一个潜在治疗靶点。
