炎症介导的EGFR由内而外调节肺腺癌侵润网络构建及对抗策略

In this project, different Pearson mutual-positive-correlation EGFR (epidermal growth factor receptor), SLC2A1 (solute carrier family 2 (facilitated glucose transporter) member), HMMR (hyaluronan-mediated motility receptor (RHAMM)), PRC1 (protein regulator of cytokinesis 1), UBE2C (ubiquitin-conjugating enzyme E2C)-activatory molecular network will be constructed from overlapping of GRNInfer and Pearson under SLC2A1, HMMR, PRC1, UBE2C CC ≥0.25 in high lung adenocarcinoma compared with low human normal adjacent tissues, respectively. The EGFR inside-out activated inflammation-induced cell motility through SLC2A1-HMMR-PRC1-UBE2C single molecular feedback, upstream and downstream network (with direct-activated relationship to molecules of the network, respectviely) will be constructed in high lung adenocarcinoma, based on integrative GRNInfer with GO, KEGG, GenMAPP, BioCarta and disease databases. The Pearson mutual-positive-correlation inhibiting-hypothesis common molecules will be selected from the overlapping of GRNInfer and Pearson under EGFR, SLC2A1, HMMR, PRC1, UBE2C CC≤-0.25 in low human normal adjacent tissues different from high lung adenocarcinoma for reverse proofing our hypothesis. The inhibiting-hypothesis common molecular feedback, upstream and downstream total activatory network will be constructed in low human normal adjacent tissues as counter-strategy of EGFR inside-out activated inflammation-induced cell motility in lung adenocarcinoma. The project is very useful to develop a new route and identify novel markers and potential drugs for prognosis and therapy of lung adenocarcinoma.

本项目拟筛选不同于正常邻近组织的高表达肺腺癌中与表皮生长因子受体（EGFR），溶质运载蛋白家族2成员1（葡萄糖转运蛋白）（SLC2A1），透明质酸介导运动因子受体（HMMR），胞质分裂调控蛋白1（PRC1），泛素结合酶E2C（UBE2C）有激活关系的GRNInfer和Pearson相关系数（CC）≥0.25重叠的两两正相关分子，整合GRNInfer和GO，KEGG等知识库，构建其反馈和上下游单分子网络（分别与本网络分子有直接激活关系）；反向验证在肺腺癌正常邻近组织与EGFR、SLC2A1、HMMR、PRC1、UBE2C有直接抑制关系的GRNInfer和Pearson CC≤-0.25重叠的两两正相关分子中提取抑制假说的共同分子，建立并分析其共同分子在肺腺癌正常邻近组织的总激活反馈和上下游网络作为炎症介导的EGFR由内而外调节肺腺癌侵润对抗策略，为肺腺癌的整合诊断和治疗奠定基础并开辟新途径。

生物分子很少单独起作用，它们倾向于成组通过网状的交互作用而影响生物系统的功能，对功能的研究就必须分析其激活和抑制分子网络，或者更准确的说，要把基因组或分子组看作一个系统来进行分析。我们构建和比较了GPSM2、GDPD5、E2F1、ABCC3、DDX3Y、CTNNA1_1、OAS1在正常和疾病中的分子网络，结果如下：GPSM2激活网络在非肿瘤肝炎/肝硬化中，显示更多的细胞核和细胞质以及较少的细胞外空隙蛋白质结合；（2）在肝癌中表现出较强的生长因子活性和较弱的胞浆酶活化剂活性；（3）在非肿瘤肝炎/肝硬化中体现较少的激活分子数量和较多抑制分子数量，然而在肝癌中显示较多的激活分子和较少的抑制分子数量；（4）在非肿瘤肝炎/肝硬化中，GPSM2信号转导网络具备更强大的转录功能；（5）在肝癌中体现更强的细胞增殖同时较弱的肌肉收缩的规律，从而提高核细胞分裂。GDPD5激活网络在肝癌中血液凝固，趋化性，炎症反应，受体介导的内吞作用，DNA修复正调节，泛素化蛋白的正调节是增强的。E2F1相互作用BRCA1的间接通路诱导肝癌细胞周期调控通过CD4+T到细胞溶质。ABCC3激活和抑制网络在肺癌中转运蛋白活性和细胞组分功能是增强的；然而ATP结合，跨膜，催化活性，剪接变体和序列变异减弱。DDX3Y激活网络在人类左脑中酶催化功能到发育和认知是增强的。CTNNA1_1激活和抑制网络在人类左脑中神经系统发育和膜功能是增强的；然而初级代谢过程，细胞器，信号转导和调节细胞过程减弱。OAS1激活网络在脑性艾滋病中的刺激反应、催化活性，细胞器，代谢过程，选择性剪接和序列变异功能是增强的。为临床诊断和药物研发奠定基础。