Adenoviral-mediated RNA interference targeting URG11 inhibits growth of human hepatocellular carcinoma
Adenoviral-mediated RNA interference targeting URG11 inhibits growth of human hepatocellular carcinoma
复制标题
腺病毒介导的RNA干扰靶向URG11抑制人肝细胞癌的生长
DOI：
10.1002/ijc.25624
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发表时间：
2011-06-15
影响因子：
6.4
通讯作者：
Fan, Daiming
中科院分区：
文献类型：
--
作者：
Fan, Rui;Li, Xiaohua;Fan, Daiming
肝细胞癌（HCC）是亚洲第二常见的恶性肿瘤，由于手术后复发率高和化疗耐药，5年生存率低于5%。各种治疗肝癌的干预措施，特别是基因治疗，最近已经在肿瘤模型系统中进行了研究，以提供对肝癌发生的更完整的理解，并有效地设计治疗策略来治疗这种疾病。在我们的研究中，我们构建了一个腺病毒载体表达小干扰RNA（siRNA）靶向一个新发现的基因命名为上调基因11（URG 11）。我们将该载体导入肝癌细胞中，以研究URG 11在肝癌发生中的作用。我们观察到，在URG 11敲低，肝癌细胞增殖抑制通过下调G1-S期相关分子，包括细胞周期蛋白D1和凋亡诱导的Bcl-2下调的结果。除了抑制cyclin D1、CDK 4、pRb和Bcl-2的表达外，URG 11还抑制包括CAPN 9在内的其他几种蛋白的表达，这一点通过cDNA微阵列和2D凝胶电泳进行了鉴定。此外，Ad-URG 11-siRNA在裸鼠中显著抑制HCC肿瘤生长。结论：Ad-URG 11-siRNA通过沉默URG 11基因在体内外均能显著抑制肝癌细胞的生长，将其用于肝癌的基因治疗可能是一种新的治疗策略。
Hepatocellular carcinoma (HCC) is the second most common malignancy in Asia, with a 5-year survival rate of less than 5% due to high recurrence after surgery and resistance to chemotherapy. A variety of therapeutic interventions to treat HCC, particularly gene therapy, have recently been investigated in tumor model systems to provide a more complete understanding of hepatocarcinogenesis and effectively design therapeutic strategies to treat this disease. In our study, we constructed an adenoviral vector expressing small interfering RNA (siRNA) targeting a newly discovered gene named upregulated gene 11 (URG11). We introduced this vector into HCC cells to investigate the role of URG11 in HCC carcinogenesis. We observed that upon URG11 knockdown, HCC cell proliferation was inhibited through downregulation of several G1-S phase related molecules including cyclin D1 and apoptosis was induced as a result of Bcl-2 downregulation. Besides decreased expression of cyclin D1, CDK4, pRb and Bcl-2, URG11 also suppressed several other proteins including CAPN9, which was identified by cDNA microarray and 2D gel electrophoresis. Moreover, Ad-URG11-siRNA significantly suppressed HCC tumor growth in nude mice. In conclusion, Ad-URG11-siRNA can significantly suppress HCC tumor growth in vitro and in vivo by silencing the URG11 gene, and the use of this vector for gene therapy may represent a novel strategy to treat human HCC.