RNA-binding protein RPS3 contributes to hepatocarcinogenesis by post-transcriptionally up-regulating SIRT1 (Retracted Article)
RNA-binding protein RPS3 contributes to hepatocarcinogenesis by post-transcriptionally up-regulating SIRT1 (Retracted Article)
复制标题
RNA结合蛋白RPS3通过转录后上调SIRT1促进肝癌发生
DOI：
10.1093/nar/gky1209
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发表时间：
2019-02-28
影响因子：
14.9
通讯作者：
Han, Limin
中科院分区：
文献类型：
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作者：
Zhao, Lijun;Cao, Jianzhong;Han, Limin
虽然一些研究表明RNA结合蛋白(RBP)在多种生理过程和癌症中起关键作用，但其详细的生物学功能和机制仍有待确定。通过使用成熟的肝细胞癌数据集进行生物信息学分析，我们确定了一组与肝癌进展相关的限制性商业惯例(HPARBPs)，并发现HPARBPs的全球表达与患者的预后显著相关。在42个HPARBP中，人核糖体蛋白S3(RPS3)是含量最丰富的基因之一，其在肝癌中的作用尚不清楚。功能获得和功能丧失分析表明，RPS3在体外和体内都促进了肝癌的发生。从机制上讲，我们发现沉默的信息调节因子1(SIRT1)是RPS3的一个关键靶点，对于维持RPS3诱导的肝癌细胞的恶性表型是必不可少的。RPS3通过与SIRT1mRNA 3非翻译区3448-3530区域的AUUUA基序结合来稳定SIRT1 mRNA。此外，我们还发现(5-甲酰呋喃-2-基)4-羟基-2-亚甲基丁酸甲酯(FMHM)通过抑制RPS3/SIRT1通路而抑制肝癌的进展。我们的研究揭示了RPS3通过转录后调控SIRT1表达促进肝癌发生的新的核糖体外作用，并提出RPS3/SIRT1通路在肝细胞癌中具有潜在的治疗靶点。
Although several studies indicate that RNA-binding proteins (RBPs) contribute to key steps in a variety of physiological processes and cancer, the detailed biological functions and mechanisms remain to be determined. By performing bioinformatics analysis using well-established hepatocellular carcinoma (HCC) datasets, we identified a set of HCC progression-associated RBPs (HPARBPs) and found that the global expression of HPARBPs was significantly correlated with patient prognosis. Among the 42 HPARBPs, human ribosomal protein S3 (RPS3) was one of the most abundant genes whose role remains uncharacterized in HCC. Gain- and loss-of-function analyses demonstrated that RPS3 promoted HCC tumorigenesis both in vitro and in vivo. Mechanistically, we revealed that silent information regulator 1 (SIRT1) was a critical target of RPS3 and was essential for sustaining the RPS3-induced malignant phenotypes of HCC cells. RPS3 stabilized SIRT1 mRNA by binding to AUUUA motifs in the 3448-3530 region of the 3 untranslated region (UTR) of SIRT1 mRNA. In addition, we found that (5-formylfuran-2-yl) methyl 4-hydroxy-2-methylenebutanoate (FMHM) inhibited HCC progression by repressing the RPS3/SIRT1 pathway. Our study unveils a novel extra-ribosomal role of RPS3 in facilitating hepatocarcinogenesis via the post-transcriptional regulation of SIRT1 expression and proposes that the RPS3/SIRT1 pathway serves as a potential therapeutic target in HCC.