Suppressing N-Myc downstream regulated gene 1 reactivates senescence signaling and inhibits tumor growth in hepatocellular carcinoma
Suppressing N-Myc downstream regulated gene 1 reactivates senescence signaling and inhibits tumor growth in hepatocellular carcinoma
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DOI：
10.1093/carcin/bgt401
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发表时间：
2014-04-01
期刊：
影响因子：
4.7
通讯作者：
So, Samuel K.
中科院分区：
文献类型：
--
作者：
Lu, Wen-Jing;Chua, Mei-Sze;So, Samuel K.
肝细胞癌是世界上第五大致死性恶性肿瘤，目前尚无有效治疗方法。为了发现潜在的新的肝癌治疗靶点，我们先前研究了肝癌患者的基因表达谱，发现N-Myc下游调节基因1(NDRG1)的显著上调与肝癌患者更具侵袭性的表型和更差的总体生存相关。在这项研究中，我们进一步使用功能丧失的方法(RNA干扰)来了解NDRG1在肝癌发生中的作用。我们发现，抑制NDRG1通过在体内外诱导肝癌细胞的广泛衰老而显著损害肝癌细胞的生长，并伴随着细胞周期停滞在G(1)期。观察到的NDRG1抑制抗肿瘤作用与主要衰老相关信号通路的激活有关，如肿瘤抑制基因p53、p21和p16的上调，以及磷酸化Rb的减少。为进一步了解NDRG1调控的衰老在肝细胞癌中的临床意义，对92例肝细胞癌患者进行了免疫组织化学染色。我们发现ndr1高表达(N 66)与低p21(n 82；P<；0.001)和低p16(n 86；P<；0.001)水平相关。综上所述，本研究表明NDRG1是一种潜在的肝癌治疗靶点，因为它的抑制通过激活糖原合成酶激酶-3P53途径而触发肝癌细胞的衰老，从而抑制肿瘤的进展。我们报道了NDRG1通过糖原合成酶激酶-3p53途径调节肝癌细胞衰老的新功能，提示抑制NDRG1是一种可能的治疗途径。
Hepatocellular carcinoma (HCC) is the fifth most lethal malignancy worldwide with no curative therapies. To discover potentially novel therapeutic targets for HCC, we previously studied the gene expression profiles of HCC patients and identified that significant upregulation of N-Myc downstream regulated gene 1 (NDRG1) is associated with more aggressive phenotypes and poorer overall survival of HCC patients. In this study, we further used a loss-of-function approach (RNA interference) to understand the role of NDRG1 in hepatocarcinogenesis. We found that suppression of NDRG1 significantly impaired HCC cell growth through inducing extensive cellular senescence of HCC cells both in vitro and in vivo, accompanied by cell cycle arrest at the G(1) phase. The observed antitumor effects of NDRG1 suppression were correlated with activation of major senescence-associated signaling pathways, such as upregulation of tumor suppressors p53, p21 and p16, and decreased phosphorylated Rb. To obtain further insights into the clinical significance of NDRG1-modulated senescence in HCC patients, immunohistochemistry staining of 92 cases of HCC patients was done. We found that high NDRG1 expression (n 66) is associated with low p21 (n 82; P < 0.001) and low p16 (n 86; P < 0.001) levels. In conclusion, this study demonstrated that NDRG1 is a potential therapeutic target for HCC because its suppression triggers senescence of HCC cells through activating glycogen synthase kinase-3p53 pathway, thereby inhibiting tumor progression.We report a novel function of NDRG1 in regulating cellular senescence in HCC cells, via glycogen synthase kinase-3p53 pathway, suggesting that NDRG1 suppression is a likely therapeutic approach.