Modeling The Signal Transduction Of IFN-γand IL-6Pathways And Eluciding The Mechanism Of Anti-cancer Drug Action On Cell Apoptosis Via System Biology Methods

Systems biology, using the strategy of systematically integrated analysis, could interpretthe interaction mechanism among different kinds of components within living organisms. Asan integrated science, systems biology needs to integrate multiple omics data, in order tosystematically describe regulatory relationships among components like genes and proteins.Mathematical modeling and omics analysis is two of the most important methods of systemsbiology. This study includes two research contents:(1) elucidating the crosstalk mechanismbetween IFN-gamma(IFN-γ) and interleukin-6(IL-6) via mathematical modelling;(2)systematically investigating the anti-cancer drug induced apoptosis via omics analysis. IFN-γexhibits the unique antiviral activity, which could promote immune activation, inhibit cellproliferation, induce apoptosis and immune response to cancer. IL-6also plays an importantrole in inflammation and immune response, which could induce the differentiation ofcytotoxic T lymphocyte differentiation, inhibit apoptosis and enhance the activity of naturalkiller cell. Previous researches confirmed that the cellular responses to IFN-γ and IL-6couldboth activate the Janus kinase/signal transducer and activator of transcription (JAK/STAT)pathway. However, the types of STAT proteins, they activated, are completed differently,which relate with the biological functions of IFN-γ inducing apoptosis and IL-6promotingcell proliferation. Moreover, the various crosstalks between IFN-γ and IL-6signals couldsignificantly influence the activation of JAK/STAT pathway and many complex diseasesinvolve the abnormal activation of JAK/STAT pathway on account of breaking the dynamicbalance between IFN-γ and IL-6signals. However, mechanisms and intrinsic kinetics of thecrosstalk between IFN-γ and IL-6signals are not yet clear. Following the development ofsystems biology, researchers begin to analyze IFN-γ and IL-6signal transductions viamathematical modelling, and successfully predict the dynamic signal responses of IFN-γ inpancreatic cancer cells and IL–6in hepatocyte. However there is still no report of elucidatingthe crosstalk mechanism between IFN-γ and IL-6via mathematical modelling. Usingestablished mathematical models, we constructed the first IFN-γ and IL-6crosstalk model.Through mathematical simulation and sensitivity analysis, we investigated the crosstalkmechanism between IFN-γ and IL-6signals. Mathematical simulations confirm the existingexperimental results, which demonstrate the effectiveness of the crosstalk model and therationality of the multi-level interaction mechanism between IFN-γ and IL-6signals.Furthermore, the crosstalk model reveals good openness and extensibility, and could beutilized to verify other possible interaction mechanism between IFN-γ and IL-6signals, which is instructive for explaining the crosstalk between other cytokines and verifying theircrosstalk model hypothesizes.The mechanism of anti-cancer drug action is to induce apoptosis within cancer cells,which have lost the balance between apoptosis and survival signals. Histone deacetylasesinhibitor (HDACi) can regulate the post-translational modification state of a variety ofhistones and nonhistones, and is confirmed to induce apoptosis response within cancer cells.Suberoylanilide hydroxamic acid (SAHA) is the first-in-class of HDACi that has beenapproved in a clinic for treating cutaneous T-cell lymphoma. As a pan-HDAC inhibitor,SAHA could wildly influence various kinds of biological functions. Therefore, the integratedanalysis of the entire genome is very important to explain the mechanism of SAHA action. Inthis study, omics analysis method is applied to investigate the gene expression data derivedfrom SAHA treated samples. We analyzed the time course variation of gene expressioncaused by anti-cancer drug, and identified cancer and normal sample specific time coursevariation pattern of gene expression coherence (TVPC) within pathways. According to thespecific time and the sample type of pathway to TVPC, we systematically elucidate themechanism of how SAHA through interfering genes related processes like DNA damage,signal pathways transduction and mitochondrial disintegration to induce intrinsic apoptosis.