Construction Of A Gene Regulatory Network Associated With Multiple Risk Factors In Clear Cell Renal Cell Carcinoma And The Dynamics Of Its Enrichment Signaling Pathway NF-?B Mediated By MiRNA

Clear cell renal cell carcinoma(ccRCC)is a common tumor of the urinary system and its pathogenesis is not clearly understood.Several studies have shown that it is associated with risk factors such as smoking,diabetes,age,obesity,hyperglycemia,overweight,gender and chronic inflammation,but no work has been done on the genetic association of cc RCC with related risk factors.Moreover,it has been shown that the transcription factor NF-?B is involved in the regulation of inflammatory mediators in kidney disease and can promote the expression of miR-146,which regulates NF-?B activity by inhibiting I?B?.This paper firstly constructs a gene regulatory network of cc RCC linked to eight risk factors,identifies new molecular markers of cc RCC and their enrichment signaling pathways,then,investigates the role of miR-146-mediated NF-?B signaling pathway in cc RCC.The second chapter of this paper is based on a systems biology approach to explore the hub genes and signaling pathways related to the occurrence,development,and prognosis of cc RCC by combining cc RCC with its associated risk factors.Firstly,the differentially expressed genes(DEGs)of cc RCC and eight risk factors were identified separately,the DEGs common to the risk factors and cc RCC respectively were studied,protein-protein interaction(PPI)networks were constructed,and hub genes were screened according to the topological properties of the networks.The prognosis analysis of hub genes by survival analysis revealed that DEGs CD44,common to cc RCC and diabetes,was associated with cc RCC prognosis and might be a new molecular marker for cc RCC.KEGG pathway enrich-ment analysis of CD44-related co-expressed genes identified Fc?r-mediated phagocytosis,metabolic pathway,and NF-?B enrichment pathway.Some studies have shown that the NF-?B signaling pathway induces CD44 overexpression,which suggests that the NF-?B signaling pathway may be involved in the development of cc RCC,which is important for the study of the NF-?B signaling pathway.In Chapter three,a new model with miR-146 feedback regulation and the transcription time delay is proposed based on the mathematical model of the NF-?B signaling pathway by Krishna et al.Firstly,the existence and stability of the positive equilibrium point of the new system are proven theoretically,then the existence of the Hopf bifurcation induced by time delay is verified.Then,numerical analysis was performed to compare the changes in the kinetic behavior of the system with and without miR-146 regulation,in which the outcome indicated that miR-146 was beneficial in suppressing the oscillatory activation of the NF-?B system.The effect of the presence or absence of time delay and the length of the time delay on the system was also analyzed,revealing that the transcriptional time delay facilitates the activation of the system and its length affects the period and amplitude of the oscillation.Then,the effects of the newly introduced parameters and time delay co-regulation on the system are discussed.The results show that the Michaelis constant J and the degradation rate d₁of miR-146 promoted by NF-?B can change the qualitative behavior of the system,and as J and d₁increase,the system changes from steady state to oscillation,which the oscillation of NF-?B is detrimental to the treatment of cc RCC.Finally,a sensitivity analysis of the system parameters was performed based on R software,which found that the system was most sensitive to miR-146on I?B?inhibition rate d₂.This chapter reveals the dynamics of miR-146-mediated NF-?B signaling pathway in cc RCC,which provides ideas for studying the biological functions of miRNAs in signaling pathways and related diseases.