Bifunctional enzyme ATIC promotes propagation of hepatocellular carcinoma by regulating AMPK-mTOR-S6 K1 signaling.
Bifunctional enzyme ATIC promotes propagation of hepatocellular carcinoma by regulating AMPK-mTOR-S6 K1 signaling.
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双功能酶ATIC通过调节AMPK-mTOR-S6 K1信号促进肝细胞癌的增殖
DOI：
10.1186/s12964-017-0208-8
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发表时间：
2017-12-16
期刊：
影响因子：
--
通讯作者：
Yin Y
中科院分区：
文献类型：
--
作者：
Li M;Jin C;Xu M;Zhou L;Li D;Yin Y
肝细胞癌（Hepatocellular carcinoma，HCC）是一种预后不良的恶性肿瘤.为了有效地治疗HCC，必须确定新的分子靶点和治疗方法。5-氨基咪唑-4-甲酰胺核糖核苷酸甲酰转移酶/肌苷一磷酸（IMP）环化水解酶（ATIC）是一种双功能蛋白酶，催化嘌呤从头生物合成途径的最后两步。ATIC是否有助于癌症的发展仍不清楚。MethodsATIC mRNA水平在不同类型的人肝癌样品或正常组织中测定基因表达跨正常和肿瘤组织（GENT）数据库。RT-PCR和western blot检测ATIC在人肝癌组织或细胞系中的表达水平。通过Kaplan-Meier分析确定ATIC低和ATIC高组中HCC患者的总生存期和无病生存期。通过慢病毒感染评估ATIC敲减对细胞增殖、细胞凋亡、集落形成和迁移的影响。通过Western blot和Compound C（C-C）rescue assays. Results.ResultsHere，我们首次证明了ATIC在HCC组织中的表达异常上调，高水平的ATIC与HCC患者的生存率相关。ATIC表达的敲低导致HCC细胞的增殖、集落形成和迁移显著减少。我们还确定了ATIC作为一种新的调节腺苷一磷酸激活蛋白激酶（AMPK）和其下游信号哺乳动物雷帕霉素靶（mTOR）。ATIC抑制AMPK激活，从而激活mTOR-S6 K1-S6信号传导，并支持HCC细胞的生长和运动活性。ConclusionTogether，我们的结果表明，ATIC作为一个致癌基因，通过靶向AMPK-mTOR-S6 K1信号传导促进生存，增殖和迁移。
BackgroundHepatocellular carcinoma (HCC) is one of the cancer types with poor prognosis. To effectively treat HCC, new molecular targets and therapeutic approaches must be identified. 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate (IMP) cyclohydrolase (ATIC), a bifunctional protein enzyme, catalyzes the last two steps of the de novo purine biosynthetic pathway. Whether ATIC contributes to cancer development remains unclear.MethodsATIC mRNA levels in different types of human HCC samples or normal tissues were determined from Gene Expression across Normal and Tumor tissue (GENT) database. The expression level of ATIC in human HCC samples or cell lines were examined by RT-PCR and western blot. Overall survival and disease-free survival of HCC patients in the ATIC low and ATIC high groups were determined by Kaplan-Meier analysis. Effects of ATIC knockdown by lentivirus infection were evaluated on cell-proliferation, cell-apoptosis, colony formation and migration. The mechanisms involved in HCC cells growth, apoptosis and migration were analyzed by western blot and Compound C (C-C) rescue assays.ResultsHere, we first demonstrated that expression of ATIC is aberrantly up-regulated in HCC tissues and high level of ATIC is correlated with poor survival in HCC patients. Knockdown of ATIC expression resulted in a dramatic decrease in proliferation, colony formation and migration of HCC cells. We also identified ATIC as a novel regulator of adenosine monophosphate-activated protein kinase (AMPK) and its downstream signaling mammalian target of rapamycin (mTOR). ATIC suppresses AMPK activation, thus activates mTOR-S6 K1-S6 signaling and supports growth and motility activity of HCC cells.ConclusionTaken together, our results indicate that ATIC acts as an oncogenic gene that promotes survival, proliferation and migration by targeting AMPK-mTOR-S6 K1 signaling.
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影响因子：
11.2
作者：
Rothbart SB;Racanelli AC;Moran RG
通讯作者：
Moran RG
影响因子：
2
作者：
Shin G;Kang TW;Yang S;Baek SJ;Jeong YS;Kim SY
通讯作者：
Kim SY
影响因子：
4.8
作者：
Rattan, R;Giri, S;Singh, I
通讯作者：
Singh, I
DOI：
10.1038/87555
发表时间：
2001-05-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Greasley, SE;Horton, P;Wilson, IA
通讯作者：
Wilson, IA
对嘌呤代谢调节的新观点：嘌呤体。
影响因子：
13.8
作者：
Pedley AM;Benkovic SJ
通讯作者：
Benkovic SJ