Small nucleolar RNA 42 acts as an oncogene in lung tumorigenesis.
Small nucleolar RNA 42 acts as an oncogene in lung tumorigenesis.
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DOI：
10.1038/onc.2011.449
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发表时间：
2012-05-31
期刊：
影响因子：
8
通讯作者：
Jiang F
中科院分区：
文献类型：
--
作者：
Mei YP;Liao JP;Shen J;Yu L;Liu BL;Liu L;Li RY;Ji L;Dorsey SG;Jiang ZR;Katz RL;Wang JY;Jiang F
非小细胞肺癌(NSCLC)是导致癌症死亡的主要原因，反映出需要更好地了解肿瘤的发生机制，并开发新的诊断和治疗靶点。新出现的证据表明，小核仁RNA(SnoRNAs)在肿瘤发生中起着不正常的作用。我们最近的研究表明，小核仁RNA42(SNORA42)在肺肿瘤中过表达。在这里，我们研究SNORA42在NSCLC肿瘤发生中的作用。我们同时评估了SNORA42及其宿主基因KIAA0907在10个非小细胞肺癌细胞系和一个人支气管上皮细胞系中的基因组剂量和表达水平。然后，我们通过功能获得和功能丧失的分析来确定SNORA42在肺癌细胞系中的体外功能意义。我们还通过尾静脉或皮下注射将SNORA42-siRNA接种到小鼠体内。最后，采用定量逆转录聚合酶链式反应(QRT-PCR)方法检测冰冻手术切除的I期非小细胞肺癌组织中SNORA42的表达水平。在肺癌细胞中经常观察到SNORA42的基因组扩增和相关的高表达，而不是KIAA0907，这表明SNORA42的过度表达是由其基因组扩增激活的。SNORA42在非小细胞肺癌细胞中被敲除，在体外和体内的致瘤性被抑制，而在支气管上皮中被增强的SNORA42表达促进了细胞的生长和集落形成。SNORA42抑制的这种多效性至少部分是通过P53依赖的方式增加NSCLC细胞的凋亡来实现的。肺癌组织标本中SNORA42的表达与NSCLC患者的生存期呈负相关。因此，SNORA42的激活可能在肺癌的发生中起到致癌作用，并为肺癌的诊断和治疗提供潜在的靶点。
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death, reflecting the need for better understanding the oncogenesis, and developing new diagnostic and therapeutic targets for the malignancy. Emerging evidence suggests that small nucleolar RNAs (snoRNAs) have malfunctioning roles in tumorigenesis. Our recent study demonstrated that small nucleolar RNA 42 (SNORA42) was overexpressed in lung tumors. Here, we investigate the role of SNORA42 in tumorigenesis of NSCLC. We simultaneously assess genomic dosages and expression levels of SNORA42 and its host gene, KIAA0907, in 10 NSCLC cell lines and a human bronchial epithelial cell line. We then determine in vitro functional significance of SNORA42 in lung cancer cell lines through gain- and loss-of-function analyses. We also inoculate cancer cells with SNORA42-siRNA into mice through either tail vein or subcutaneous injection. We finally evaluate expression level of SNORA42 on frozen surgically resected lung tumor tissues of 64 patients with stage I NSCLC by using quantitative reverse transcriptase PCR assay. Genomic amplification and associated high expression of SNORA42 rather than KIAA0907 are frequently observed in lung cancer cells, suggesting that SNORA42 overexpression is activated by its genomic amplification. SNORA42 knockdown in NSCLC cells inhibits in vitro and in vivo tumorigenicity, whereas enforced SNORA42 expression in bronchial epitheliums increases cell growth and colony formation. Such pleiotropy of SNORA42 suppression could be achieved at least partially through increased apoptosis of NSCLC cells in a p53-dependent manner. SNORA42 expression in lung tumor tissue specimens is inversely correlated with survival of NSCLC patients. Therefore, SNORA42 activation could have an oncogenic role in lung tumorigenesis and provide potential diagnostic and therapeutic targets for the malignancy.