Increased RNA-induced silencing complex (RISC) activity contributes to hepatocellular carcinoma.
Increased RNA-induced silencing complex (RISC) activity contributes to hepatocellular carcinoma.
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DOI：
10.1002/hep.24216
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发表时间：
2011-05
期刊：
影响因子：
13.5
通讯作者：
Sarkar, Devanand
中科院分区：
文献类型：
--
作者：
Yoo, Byoung Kwon;Santhekadur, Prasanna K.;Gredler, Rachel;Chen, Dong;Emdad, Luni;Bhutia, Sujit;Pannell, Lewis;Fisher, Paul B.;Sarkar, Devanand
对于晚期肝细胞癌（HCC）几乎没有有效的治疗方法，需要确定新的靶点以开发有效的治疗方法。我们最近发现，癌基因星形胶质细胞升高基因-1（AEG-1）在肝癌发生中起着重要作用。采用酵母双杂交试验和免疫共沉淀，然后质谱，我们确定了葡萄球菌核酸酶域1（SND 1），在RNA诱导的沉默复合物（RISC）促进RNAi介导的基因沉默的核酸酶，作为AEG-1相互作用蛋白。免疫共沉淀和共定位研究证实，AEG-1也是RISC的一个组成部分，AEG-1和SND 1都是最佳RISC活性所必需的，有助于siRNA和miRNA介导的荧光素酶报告基因沉默。在109例人HCC样本中，与正常肝脏相比，SND 1在约74%的病例中过表达。相应地，与永生的正常肝细胞相比，在人HCC细胞中观察到显著更高的RISC活性。由AEG-1或SND 1赋予的RISC活性增加导致作为oncomiR靶点的肿瘤抑制基因mRNA的降解增加。抑制SND 1的酶活性可显着抑制人肝癌细胞的增殖。作为一个必然的结果，SND 1的稳定过表达增强和siRNA介导的抑制SND 1废除人肝癌细胞在体外和体内的生长，从而揭示了SND 1在肝癌发生中的潜在作用。我们揭示了一种新的机制，即AEG-1和SND 1的过表达导致RISC活性增加可能有助于肝癌的发生。靶向抑制SND 1酶活性可能成为肝癌的有效治疗方法。
There is virtually no effective treatment for advanced hepatocellular carcinoma (HCC) and novel targets need to be identified to develop effective treatment. We recently documented that the oncogene Astrocyte elevated gene-1 (AEG-1) plays a seminal role in hepatocarcinogenesis. Employing yeast two-hybrid assay and co-immunoprecipitation followed by mass spectrometry we identified Staphylococcal nuclease domain containing 1 (SND1), a nuclease in the RNA-induced silencing complex (RISC) facilitating RNAi-mediated gene silencing, as an AEG-1 interacting protein. Co-immunoprecipitation and co-localization studies confirmed that AEG-1 is also a component of RISC and both AEG-1 and SND1 are required for optimum RISC activity facilitating siRNA and miRNA-mediated silencing of luciferase reporter gene. In 109 human HCC samples SND1 was overexpressed in ∼74% cases compared to normal liver. Correspondingly, significantly higher RISC activity was observed in human HCC cells compared to immortal normal hepatocytes. Increased RISC activity, conferred by AEG-1 or SND1, resulted in increased degradation of tumor suppressor mRNAs that are target of oncomiRs. Inhibition of enzymatic activity of SND1 significantly inhibited proliferation of human HCC cells. As a corollary, stable overexpression of SND1 augmented and siRNA-mediated inhibition of SND1 abrogated growth of human HCC cells in vitro and in vivo thus revealing a potential role of SND1 in hepatocarcinogenesis. We unravel a novel mechanism that overexpression of AEG-1 and SND1 leading to increased RISC activity might contribute to hepatocarcinogenesis. Targeted inhibition of SND1 enzymatic activity might be developed as an effective therapy for HCC.
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影响因子：
50.3
作者：
Hu G;Chong RA;Yang Q;Wei Y;Blanco MA;Li F;Reiss M;Au JL;Haffty BG;Kang Y
通讯作者：
Kang Y
DOI：
10.1073/pnas.0910936106
发表时间：
2009-12-15
影响因子：
11.1
作者：
Emdad, Luni;Lee, Seok-Geun;Fisher, Paul B.
通讯作者：
Fisher, Paul B.
影响因子：
3.3
作者：
Didiot, Marie-Cecile;Subramanian, Murugan;Moine, Herve
通讯作者：
Moine, Herve
影响因子：
4.4
作者：
Ho, Jiapei;Kong, Jacklyn-Wai-Fun;Lim, Yoon-Pin
通讯作者：
Lim, Yoon-Pin
DOI：
10.1016/j.bbrc.2008.04.084
发表时间：
2008-06-27
影响因子：
3.1
作者：
Ash, S. C.;Yang, D. Q.;Britt, D. E.
通讯作者：
Britt, D. E.