Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis.
Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis.
复制标题
FBXW7 环状 RNA 在抑制神经胶质瘤肿瘤发生中的新作用。
DOI：
10.1093/jnci/djx166
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发表时间：
2018-03-01
期刊：
影响因子：
--
通讯作者：
Zhang N
中科院分区：
文献类型：
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作者：
Yang Y;Gao X;Zhang M;Yan S;Sun C;Xiao F;Huang N;Yang X;Zhao K;Zhou H;Huang S;Xie B;Zhang N
环状RNA（circRNA）是广泛存在于真核生物基因组中的RNA转录物。最近的证据表明circRNA在组织发育、基因调控和癌发生中起重要作用。然而，尽管最近报道了几种circRNA的翻译，但circRNA是否编码功能蛋白仍然难以捉摸。通过使用10个病理诊断的胶质母细胞瘤样品及其配对的相邻正常脑组织进行CircRNA深度测序。采用北方印迹、桑格测序、抗体和液相色谱串联质谱仪等方法证实了两种细胞系中存在circ-FBXW 7及其编码蛋白。慢病毒转染的稳定U251和U373细胞用于评估新蛋白质在体外和体内的生物学功能（每组5只小鼠）。通过使用定量聚合酶链反应（双侧对数秩检验）在38个病理诊断的胶质母细胞瘤样品及其配对的外周正常脑组织中评估circ-FBXW 7的临床意义。Circ-FBXW 7在正常人脑中大量表达（每百万映射读段的每内切酶读段[RPKM] = 9.31）。FBXW 7的跨连接开放阅读框架由内部核糖体进入位点驱动，编码一种新的21-kDa蛋白，我们将其命名为FBXW 7 - 185 aa。FBXW 7 - 185 aa在癌细胞中的上调抑制增殖和细胞周期加速，而FBXW 7 - 185 aa的敲低促进体外和体内恶性表型。FBXW 7 - 185 aa通过拮抗USP 28诱导的c-Myc稳定化而降低c-Myc的半衰期。此外，与其配对的肿瘤相邻组织相比，成胶质细胞瘤临床样品中的circ-FBXW 7和FBXW 7 - 185 aa水平降低（P < .001）。Circ-FBXW 7表达与胶质母细胞瘤患者的总生存率呈正相关（P = .03）。内源性circRNA编码人类细胞中的功能蛋白，circ-FBXW 7和FBXW 7 - 185 aa在脑癌中具有潜在的预后意义。
Circular RNAs (circRNAs) are RNA transcripts that are widespread in the eukaryotic genome. Recent evidence indicates that circRNAs play important roles in tissue development, gene regulation, and carcinogenesis. However, whether circRNAs encode functional proteins remains elusive, although translation of several circRNAs was recently reported. CircRNA deep sequencing was performed by using 10 pathologically diagnosed glioblastoma samples and their paired adjacent normal brain tissues. Northern blotting, Sanger sequencing, antibody, and liquid chromatograph Tandem Mass Spectrometer were used to confirm the existence of circ-FBXW7 and its encoded protein in in two cell lines. Lentivirus-transfected stable U251 and U373 cells were used to assess the biological functions of the novel protein in vitro and in vivo (five mice per group). Clinical implications of circ-FBXW7 were assessed in 38 pathologically diagnosed glioblastoma samples and their paired periphery normal brain tissues by using quantitative polymerase chain reaction (two-sided log-rank test). Circ-FBXW7 is abundantly expressed in the normal human brain (reads per kilobase per million mapped reads [RPKM] = 9.31). The spanning junction open reading frame in circ-FBXW7 driven by internal ribosome entry site encodes a novel 21-kDa protein, which we termed FBXW7-185aa. Upregulation of FBXW7-185aa in cancer cells inhibited proliferation and cell cycle acceleration, while knockdown of FBXW7-185aa promoted malignant phenotypes in vitro and in vivo. FBXW7-185aa reduced the half-life of c-Myc by antagonizing USP28-induced c-Myc stabilization. Moreover, circ-FBXW7 and FBXW7-185aa levels were reduced in glioblastoma clinical samples compared with their paired tumor-adjacent tissues (P < .001). Circ-FBXW7 expression positively associated with glioblastoma patient overall survival (P = .03). Endogenous circRNA encodes a functional protein in human cells, and circ-FBXW7 and FBXW7-185aa have potential prognostic implications in brain cancer.