| 引用本文格式: Guo Zhen-Yu,Zhao Xin-Jun,Ma Jun-Ren. Nogo-B and JCAD induce activation of hepatocellular carcinoma gene [J]. J. At. Mol. Phys., 2022, 39: 041003 (in Chinese) [郭阵雨,赵新军,马军仁. Nogo-B与JCAD诱导肝癌基因激活 [J]. 原子与分子物理学报, 2022, 39: 041003] |
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| Nogo-B与JCAD诱导肝癌基因激活 |
| Nogo-B and JCAD induce activation of hepatocellular carcinoma gene |
| 摘要点击 134 全文点击 9 投稿时间：2021-03-12 修订日期：2021-03-30 |
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| DOI编号
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| 中文关键词
Nogo-B与JCAD 肝癌基因 激活 |
| 英文关键词
Nogo-B and JCAD hepatocellular carcinoma gene activation |
| 基金项目
国家自然科学基金 |
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| 中文摘要
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| 基于 Hill 动力学结合 Michaelis-Menten 方程，本文建立理论模型研究 Nogo-B 蛋白与JCAD 蛋白诱导肝癌(HCC)基因激活。理论模型考虑：(1) Nogo-B 诱导 oxLDL 蛋白降解，降解的 oxLDL(DoxLDL) 通过促进 LPA(Lysopho-sphatidic acid) 合成而激活 HCC 基因表达；(2) JCAD 与 LATS2 激酶相互作用调节 YAP 蛋白磷酸化，进而激活 Hippo 信号通路中与肿瘤形成相关的增殖因子，导致 HCC 的发生发展。研究发现，oxLDL 在很短的时间内降解，DoxLDL 会很快激活下游级联通路信号(LPC、ATX、LPA等)，在很大程度上提升了 Hippo 信号通路中 YAP 的活性，进而激活下游癌基因(CTGF等)的表达。Nogo-B 通过与 ATG5 蛋白相互作用调节 oxLDL 的降解，ATG5 放大了 Nogo-B 表达信号，使得 Nogo-B 的激活表达效应增强，促进了大量的 LPA 合成并激活 YAP。CEBPβ 蛋白呈现的脉冲式信号也会增强 Nogo-B 的表达水平，YAP 和 CTGF 随 Nogo-B 表达水平的变化都呈现了趋于不变的稳态，这进一步表明了 Nogo-B 表达上调诱导的 oxLDL 降解，激活了稳定的 DoxLDL-Nogo-B-YAP-CTGF 通路。通过分析 JACD 与 LATS2 的调节作用，我们发现，JACD 抑制 YAP 磷酸化，较大程度地促使 CTGF 的表达水平上调；LATS2 则促进 YAP 磷酸化，进而在一程度上抑制 CTGF 等增殖因子的表达。理论结果符合实验，进一步深刻揭示了非酒精性脂肪肝炎(NASH)诱发 HCC 的致病机理。 |
| 英文摘要
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| Based on Hill kinetics and Michaelis-Menten function, we investigate Nogo-B and JCAD induce activation of hepatocellular carcinoma(HCC) gene. The theoretical model considers: (1) Nogo-B promotes the degradation of oxLDL by interacting with ATG5, and degraded oxLDL(DoxLDL) enhances the YAP activity in Hippo signaling pathway, which activates the expression of oncogenes(CTGF) by promoting the production of a large amount of LPA(Lysopho-sphatidic acid); (2) JCAD interacts with LATS2 to regulate phosphorylation of YAP. Dephosphorylated YAP activates tumor-related proliferation factors in the Hippo signaling pathway, in turn upregulating of activation of YAP to promote HCC cell proliferation. We found that oxLDL degrades in a short time. The degradation of oxLDL promotes LPA largely, and then promotes the activation of YAP in Hippo signaling pathway. During this process, DoxLDL will quickly activate a large number of inactivated cascade path signals (LPC, ATX, LPA, etc.), which activate expression of HCC gene. By analyzing the temporal evolutions of the levels of Nogo-B, it can be found that Nogo-B and ATG5 forms a complex NA. The ATG5 amplifies the signal of Nogo-B expression. It makes Nogo-B-enhanced activation expression, which promotes LPA production and activates YAP. A pulsed signal driven by the CEBPβ will also enhance the transcriptional activation of Nogo-B. The YAP and CTGF showed a steady state with the change of Nogo-B. This indicates further that oxLDL degradation induced by up-regulation of Nogo-B expression activates the stable oxLDL-Nogo-B-YAP-CTGF pathway. Hippo signaling is highly activated after ectopic Nogo-B expression. By analyzing the regulatory effects with the JACD and kinase LATS2, we found that JACD inhibits YAP phosphorylation, which greatly increases the expression level of CTGF. It is opposite to the effect of JCAD regulation, LATS2 promotes YAP phosphorylation, and then decreased the expression of CTGF and other proliferation factors. Our theoretical results are consistent with the experimental observations, and provide a fundamental understanding of the Non-alcoholic steatohepatitis(NASH) inducing HCC. |
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