摘要
本文从GEO数据库GSE10140-10141的225个肝癌组织高显著性表达分子中分别筛选出甲状旁腺激素(PTHLH)的四个单分子网络即低表达感染HBV或HCV的非肿瘤肝炎及肝硬化组织激活与抑制网络,高表达肝癌组织的激活与抑制网络。建立四个分子网络的GO数据库,分别从整体上比较非肿瘤肝炎及肝硬化组织与肝癌各激活组和抑制组分子网络GO生物过程的差异。进一步计算四个网络各自的上、下游或反馈生物过程,上下游反馈整合分析各激活组和抑制组分子网络整体比较后的GO生物过程,确定各功能及其特殊机制并提出假说,验证假说通过相应的其他生物过程或重复出现的次数(倍数≥2)或其上下游、反馈网络。利用GRNInfer和自编程序构建各功能和机制的新分子网络,为肝癌组织的诊断和治疗研究奠定基础。
本博士论文研究课题受到国家自然基金项目(NO.60871100)资助,部分科研成果在包括Integrative Biology, Cell Biochemistry and Biophysics, Immunologic Research, Journal of Cellular Biochemistry, Cellular Physiology and Biochemistry, Cell Proliferation, Journal of Molecular Neuroscience, Journal of inflammation, Tumor Biology, Cellular and Molecular Neurobiology, Cell Biochemistry and Function, Journal of Receptors and Signal Transduction等国际主流学术期刊上发表论文21余篇,其中,SCI检索16篇,第一作者或与导师并列第一作者论文14篇,引用次数82余次。
论文的主要工作是从六个方面上下游反馈整合比较分析了四个单分子网络的GO生物过程,确定并构建了26个特有功能和机制新网络,如下所示:
上下游反馈整合比较分析激活的PTHLH在非肿瘤肝炎及肝硬化组织和肝癌的相同,构建了非肿瘤肝炎及肝硬化组织中5个激活的PTHLH网络:反馈的有丝分裂与下游的DNA复制诱导缓慢增长细胞数目网络、偶联下游的腺苷酸环化酶到雄激素受体信号诱导细胞间粘附网络、耦合反馈的磷酸肌醇到G蛋白受体信号诱导细胞分化网络、耦合下游的正调节蛋白质泛素化到复制后修复诱导上皮细胞分化网络、耦合下游的负调节Wnt受体信号到脂肪酸合成诱导调节细胞凋亡网络。
上下游反馈整合比较分析激活的PTHLH在肝癌组织和非肿瘤肝炎及肝硬化的相同,构建了肝癌组织中6个激活的PTHLH网络:反馈的有丝分裂和DNA复制诱导快速增长细胞数目网络、上游的白细胞迁移介导的雄激素受体信号诱导细胞运动网络、耦合下游的腺苷酸环化酶到正调节IKB激酶/NFκB级联反应诱导趋化性网络、耦合反馈的磷酸肌醇到G蛋白受体信号诱导细胞粘附网络、上游的DNA损伤应答介导的正调节从蛋白质泛素化偶联复制后修复到转录诱导正调节生存基因网络、耦合负调节从上游的脂肪酸合成和Wnt受体信号到下游的肽酶诱导细胞凋亡网络。
上下游反馈整合比较分析激活的PTHLH在非肿瘤肝炎及肝硬化组织和肝癌的不同,构建了非肿瘤肝炎及肝硬化组织中2个激活的PTHLH网络:耦合上游的正调节表皮生长因子受体信号通路到蛋白运输诱导细胞衰老网络、耦合下游的微管解聚到中间纤维细胞骨架组装和合成诱导胞吐网络。
上下游反馈整合比较分析激活的PTHLH在肝癌组织和非肿瘤肝炎及肝硬化的不同,构建了肝癌组织中5个激活的PTHLH网络:上游的药物应答介导的蛋白质异戊二烯化和分泌偶联转化生长因子p和环-磷酸鸟嘌呤信号到DNA代谢诱导正调节微管聚合网络、下游的中性粒细胞免疫介导的MAPK,磷脂酶A2和NFκB活化偶联钾离子运输到脂质代谢到肌动蛋白丝组装诱导调节血管新生网络、耦合反馈的微管细胞骨架组织到核酸代谢诱导调节细胞生长网络、下游的正调节免疫球蛋白和自然杀伤、肥大、T细胞毒介导的Rho信号耦合钙离子运输诱导正调节细胞凋亡网络、耦合上游的负调节caspase,微管解聚和转录诱导抗细胞凋亡网络。
上下游反馈整合比较分析抑制的PTHLH在非肿瘤肝炎及肝硬化组织和肝癌组织的不同,构建了非肿瘤肝炎及肝硬化组织中3个抑制的PTHLH网络:下游的白细胞粘附介导的蛋白氨基酸N-连接糖基化偶联Notch和JAK-STAT级联信号到铁硫簇装配诱导衰老网络、下游的应激反应介导的调节胰岛素分泌到液体表面张力诱导调节细胞间粘附网络、耦合下游的负调节细胞粘附,有丝分裂细胞周期间的泛素连接酶和内皮细胞分化诱导抗细胞凋亡网络。
上下游反馈整合比较分析抑制的PTHLH在肝癌组织和非肿瘤肝炎及肝硬化的不同,构建了肝癌组织中5个抑制的PTHLH网络:上游的T细胞介导的细胞因子,代谢能谷氨酸受体和NFκB启动激酶信号偶联硫酸角质素和多糖代谢到中间纤维细胞骨架组装诱导细胞成熟网络、下游的胰岛素刺激介导的葡萄糖输入耦联T细胞稳态到胞吞诱导生长网络、耦合反馈的微管解聚到胶原原纤维组织诱导细胞-基质粘附网络、耦合下游的正调节表皮生长因子受体,成纤维细胞生长因子受体,MAPKKK级联,Notch, smoothened和IKB激酶/NFκB级联信号到类固醇合成诱导调节生长网络、耦合下游的负调节表皮生长因子受体,脂蛋白脂酶,MAPK, Ras信号和姐妹染色单体凝集诱导启动细胞凋亡网络。
In this study, parathyroid hormone-like hormone (PTHLH) four single molecular networks, which are activated and inhibited networks in no-tumor hepatitis/cirrhotic tissues, activated and inhibited networks in human hepatocellular carcinoma (HBV or HCV infection)(HCC), were selected from225significant high expression (fold change≥2) molecules of HCC compared with low expression of no-tumor hepatitis/cirrhotic tissues in GEO database GSE10140-10141, respectively. Four single molecular networks were computed biological processes and occurrence numbers of gene ontology (GO) in no-tumor hepatitis/cirrhotic tissues and HCC for finding new biomarkers of diagnosis and therapy in hepatocellular carcinoma. Calculating the four networks on their respective upstream, downstream or feedback biological processes and comparing GO biological processes differences of the activation and inhibition groups molecular network, we proposed and constructed the specific functions and mechanisms new molecular networks by gene regulatory network inference method and our programming. Our hypothesis was verified within other biological processes or multi-occurrence numbers (≥2) of the corresponding network, between the corresponding up-and down-stream and feedback networks, respectively.
This work was supported by the National Natural Science Foundation of China (NO.60871100).21academic papers including16SCI, cited more than82times, have been published on international academic journals. Such as:Integrative Biology, Cell Biochemistry and Biophysics, Immunologic Research, Journal of Cellular Biochemistry, Cellular Physiology and Biochemistry, Cell Proliferation, Journal of Molecular Neuroscience, Journal of inflammation, Tumor Biology, Cellular and Molecular Neurobiology, Cell Biochemistry and Function, Journal of Receptors and Signal Transduction.
The same and different biological processes were computed by up-and down-stream and feedback integrative comparisons between activated and inhibited PTHLH GO network of no-tumor hepatitis/cirrhotic tissues and the corresponding GO network of HCC. We totally proposed and constructed26networks as follows:
The same activated PTHLH GO network of no-tumor hepatitis/cirrhotic tissues by up-and down-stream and feedback integrative comparisons with the corresponding HCC: feedback mitosis and downstream DNA replication-induced slow increase of cell numbers network; coupling downstream adenylate cyclase to androgen receptor signal-induced cell-cell adhesion network; coupling feedback phosphoinositide to G-protein receptor signal-induced cell differentiation network; coupling downstream positive regulation of protein ubiquitination to postreplication repair-induced epithelial cell differentiation network; coupling downstream negative regulation of Wnt receptor signal and fatty acid biosynthesis-induced regulation of apoptosis network.
The same activated PTHLH GO network of HCC by up-and down-stream and feedback integrative comparisons with the corresponding no-tumor hepatitis/cirrhotic tissues:feedback mitosis and DNA replication-induced fast increase of cell numbers network; upstream leukocyte migration mediated-androgen receptor signal-induced cell motility network; coupling downstream adenylate cyclase activating pathway to positive regulation of I-kappaB kinase/NF-kappaB-induced chemotaxis network; coupling feedback phosphoinositide to G-protein receptor signal-induced cell adhesion network; upstream DNA damage response mediated-positive regulation of protein ubiquitination coupling postreplication repair to transcription-induced positive regulation of survival gene product activity network; coupling upstream negative regulation of fatty acid biosynthesis and Wnt receptor signal to downstream peptidase activity-induced apoptosis network.
The different activated PTHLH GO network of no-tumor hepatitis/cirrhotic tissues by up-and down-stream and feedback integrative comparisons with the corresponding HCC:coupling upstream positive regulation of EGFR signal to protein transport-induced cell aging network; coupling downstream microtubule depolymerization to intermediate filament cytoskeleton organization and biogenesis-induced exocytosis network.
The different activated PTHLH GO network of HCC by up-and down-stream and feedback integrative comparisons with the corresponding no-tumor hepatitis/cirrhotic tissues:upstream drug response-mediated protein prenylation and secretion coupling TGFβ and cGMP to DNA metabolism-induced positive regulation of microtubule polymerization network; downstream neutrophil immunity-mediated MAPK, phospholipase A2, NF-kappaB activation coupling potassium ion transport to lipid metabolism to actin filament organization-induced regulation of angiogenesis network; coupling feedback microtubule cytoskeleton organization to nucleic acid metabolism-induced regulation of cell growth network; downstream positive regulation of natural killer, immunoglobulin, mast and T cell cytotoxicity-mediated Rho signal coupling calcium ion transport-induced positive regulation of apoptosis network; coupling upstream negative regulation of caspase and microtubule depolymerization and transcription-induced anti-apoptosis network.
The different inhibited PTHLH GO network of no-tumor hepatitis/cirrhotic tissues by up-and down-stream and feedback integrative comparisons with the corresponding HCC:downstream leukocyte adhesion-mediated protein amino acid N-linked glycosylation coupling Notch and JAK-STAT cascade to iron-sulfur cluster assembly-induced aging network; downstream stress response-mediated regulation of insulin secretion to liquid surface tension-induced regulation of cell-cell adhesion network; coupling downstream negative regulation of cell adhesion, ubiquitin ligase activity during mitotic cell cycle and endothelial cell differentiation-induced anti-apoptosis network.
The different inhibited PTHLH GO network of HCC by up-and down-stream and feedback integrative comparisons with the corresponding no-tumor hepatitis/cirrhotic tissues:upstream T cell-mediated cytokine, metabotropic glutamate receptor and NF-kappaB-inducing kinase signal coupling keratan sulfate and polysaccharide metabolism to intermediate filament cytoskeleton organization-induced cell maturation network; downstream insulin stimulus mediated-glucose import coupling T cell homeostasis to endocytosis-induced growth network; coupling feedback microtubule depolymerization to collagen fibril organization-induced cell-matrix adhesion network; coupling downstream positive regulation of EGFR, FGFR, MAPKKK, Notch, smoothened signal and I-kappaB kinase/NF-kappaB cascade to steroid biosynthesis-induced regulation of growth network; coupling downstream negative regulation of EGFR, lipoprotein lipase, MAPK, Ras signal and sister chromatid cohesion-induced induction of apoptosis network.
引文
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