Network Analysis About Gene And MicroRNA In Leukemia

Since cancer is found, it has been accompanied with people for long years. To date, it isstill difficult to cure for human. MicroRNA(miRNA) is a endogenous, non-coding, containingabout22nucleotide(nt), single-stranded RNA molecule. It is involved in the occurrence anddevelopment of cancer. This work focused on four kinds of leukemia (acute lymphoblasticleukemia (ALL), acute myelogenous leukemia (AML), chronic lymphoblastic leukemia (CLL)and chronic myelogenous leukemia (CML)). Based on systems biology theory, genes andmiRNAs in leukemia, we constructed abnormal expression networks of four kinds ofleukemia separately, and related networks of four kinds of leukemia separately. We tried toreveal the pathogenesis, strategy of prevention and treatment in leukemia. At last, wecompared and analyzed four abnormal expression networks of four kinds of leukemia. It isaim at finding some common characteristics and own characteristics in different leukemia.We constructed a regulatory network, which is consisted of genes and miRNAs andbased on experimental data. Based on leukemia-related genes and miRNAs, we constructedabnormal expression networks and related networks of four kinds of leukemia. From genesand miRNAs aspects, we described the regulatory relations of leukemia. The abnormalnetworks reveal a part of pathogenesis of leukemia. We analyzed these regulatory pathways inabnormal network of four kinds of leukemia. During my PhD’s studies, I published twelverelated papers.When cancer happens, some genes and miRNAs show abnormal expression. Theseabnormal expressed genes and miRNAs are important characters when cancer happens. Thereare many regulatory relations between genes and miRNAs. These genes, miRNAs and theirrelations form a biological regulatory network. In this work, the regulatory network that isconsisted of abnormal genes and miRNAs is called cancer abnormal expression network. Inthe abnormal network, the regulatory relations between abnormal genes and miRNAs may bethe pathways when cancer happens. So if we want to find the transcription process aboutcancer, reveal the pathogenesis of cancer, we need to focus on abnormal expression network,by studying and analyzing these regulatory networks, we will understand the transcriptionprocess of cancer.In this work, all regulatory relations about genes and miRNAs are from experimentallyvalidated data. All leukemia-related genes and miRNA are from literature and authorityresource. The genes and miRNAs presented in abnormal network may have close relationwith occurrence of leukemia. So the studying about abnormal network will play an importantrole on exploring the pathogenesis of leukemia. In this work, we manually collected and dealted with leukemia-related genes andmiRNAs in four kinds of leukemia. According to their validated regulatory relations, weconstructed abnormal network and related network about four kinds of leukemia. Theabnormal network reveals a part of transcription mechanism of four kinds of leukemia. Ifthese abnormal networks are changed to normal networks, it will result in leukemia won’toccurrence. The regulation about genes and miRNAs in abnormal network may be a schemeon gene therapy in leukemia.We compared and analyzed four abnormal networks about acute lymphoblastic leukemia,acute myelogenous leukemia, chronic lymphoblastic leukemia and chronic myelogenousleukemia. As a result, we found the common genes and miRNAs in four kinds of leukemia, inaddition, we found the common regulatory pathways and typical regulatory pathways fromgenes and miRNAs aspects in different leukemia.Comparing with four abnormal networks, we found TP53, BCL2, miR-155, miR-92a-1,miR-181a-1and miR-181a-2present in four abnormal networks, meanwhile we also foundthat TP53regulates miR-155, miR-181a-1and miR-181a-2regulate BCL2in four abnormalnetworks. For studying the common regulatory pathway and typical regulatory pathway fromgenes and miRNAs aspects in four kinds of leukemia, we divided them into four groups: acuteleukemia (AML vs ALL), chronic leukemia (CLL vs CML), lymphoblastic leukemia (ALL vsCLL), myelogenous leukemia (AML vs CML).After comparing AML with ALL, we found11abnormal genes and18abnormalmiRNAs are present in two abnormal networks. NRAS and BCL2are present in twoabnormal networks, in addition, they have different regulatory pathways in two abnormalnetworks. In ALL, miR-18a targets KRAS, but in AML, miR-126, miR-96, miR-181c, let-7e,let-7a, let-7c target KRAS, miR-155targets KRAS in two abnormal networks. In ALL, BCL2is targeted by miR-20a and miR-17, but in AML, BCL2is targeted by miR-29a, miR-29b,miR-29c, miR-181b-1, miR-181b-2, miR-34b, miR-34c, miR-181c, let-7a-1, let-7a-2, let-7a-3,miR-15b, miR-204and miR-21. MiR-195, miR-125b-1, miR-451a, miR-181a-1andmiR-181a-2target BCL2in two abnormal networks. Meanwhile, we found miR-155,miR-125b-1, miR-9-1, miR-9-2and let-7b are present in two abnormal networks, and theyhave different regulatory pathways in these abnormal networks. In ALL, BCR regulatesmiR-155, miR-155targets MSH2and PICALM. In AML, IRF1and SPI1regulate miR-155,miR-155targets CSF1R, SPI1, FOXO3, FLI1, SHIP, MEIS1, PODXl and CBFB. TP53regulates miR-155and miR-155targets KRAS in two abnormal networks. In ALL,miR-125b-1targets CYP1A1, but in AML, CDX2regulates miR-125b-1, miR-125b-1targetsCDKN2A and CBFB. MiR-125b-1targets BCL2，TP53and miR-125b-1form feed-backLoopin two abnormal networks. In ALL, TNF regulates miR-9-1and miR-9-2, but in AML,CREB1regulates miR-9-2，miR-9-1and miR-9-2target CDX2. In ALL, let-7b targetsCCND2, but in AML, let-7b targets CBFB. Let-7b targets NRAS and KRAS in two abnormal networks.After comparing CLL with CML, we found7abnormal genes and8abnormal miRNAsare present in two abnormal networks. BCL2is present in two abnormal networks and it hasdifferent regulatory pathways in two abnormal networks. In CLL, BCL2is targeted bymiR-16-1, miR-16-2, miR-34a, miR-34b, miR-34c, miR-15a, miR-15b, miR-125b-1,miR-125b-2, miR-143, miR-181b, miR-21, miR-29a, miR-29b, miR-29c, but in CML, BCL2is targeted by miR-20a and miR-451a. MiR-181c, miR-181a-1and miR-181a-2target BCL2in two abnormal networks. Meanwhile, miR-155and miR-17are present in two abnormalnetworks, and they have different regulatory pathways in two abnormal networks. In CLL,miR-17targets MYC, CCND1, CDKN1A, BIM and NPAT, miR-17is regulated by MYC,CCND1and TNF. In CML, miR-17targets RB1, MAPK9, IL8and RUNX1, miR-17targetsBCL2in two abnormal networks. In CLL, miR-155targets CTLA-4, CCND1, MYB, LPL,TNFRSF10A, MYD88and LDOC1, miR-155is regulated by MYB and AKT1. In CML,miR-155targets RHOA and KRAS, miR-155is regulated by SPI1and SMAD4. TP53regulates miR-155in two abnormal networks.After comparing ALL with CLL, we found4abnormal genes and9abnormal miRNAsare present in two abnormal networks. BCL2is present in two abnormal networks and it hasdifferent regulatory pathways in two abnormal networks. In ALL, BCL2is targeted bymiR-451a, miR-20a and miR-195, but in CLL, BCL2is targeted by miR-34a, miR-34b,miR-34c, miR-16-1, miR-16-2, miR-15a, miR-15b, miR-181b, miR-181c, miR-143, miR-21,miR-29a, miR-29b, miR-29c. MiR-17, miR-125b-1, miR-125b-2, miR-181a-1andmiR-181a-2target BCL2in two abnormal networks. Meanwhile, miR-125b-1, miR-125b-2,miR-155and miR-17are present in two abnormal networks, and they have differentregulatory pathways in two abnormal networks. In CLL, miR-17targets MYC, CCND1,CDKN1A, BIM and NPAT, miR-17is regulated by MYC and CCND1, but in ALL, miR-17targets PTEN and RUNX1. TNF regulates miR-17, miR-17targets BCL2in two abnormalnetworks. In ALL, miR-125b-1and miR-125b-2target CYP1A1, but in CLL, miR-125b-1and miR-125b-2target AKT1, IRF4, BAK1, CDKN2A, DICER1, BCL3, CDK6, HMGA2and ERBB2, miR-125b-1and miR-125b-2are regulated by AKT1. MiR-125b-1andmiR-125b-2target BCL2and TP53, TP53regulates miR-125b-1and miR-125b-2in twoabnormal networks. In CLL, miR-155targets CTLA-4, SOCS1, CCND1, MYB, LPL,TNFRSF10A, MYD88and LDOC1, miR-155is regulated by MYB and AKT1, but in ALL,miR-155targets MSH2, KRAS and PICALM, miR-155is regulated by BCR. TP53regulatesmiR-155in two abnormal networks.After comparing AML with CML, we found23abnormal genes and12abnormalmiRNAs are present in two abnormal networks. BCL2and KRAS are present in twoabnormal networks and they have different regulatory pathways in two abnormal networks. InAML, BCL2is targeted by miR-29a, miR-29b, miR-29c, miR-125b-1, miR-125b-2,miR-181b-1, miR-181b-2, miR-34b, miR-34c, let-7a-1, let-7a-2, let-7a-3, miR-15b, miR-195, miR-204and miR-21, but in CML, BCL2is targeted by miR-20a and miR-17. MiR-451a,miR-181a-1, miR-181a-2and miR-181c target BCL2in two abnormal networks. In AML,KRAS is targeted by let-7a-1, let-7a-2, let-7a-3, let-7b, let-7c, let-7e, miR-96and miR-126,but in CML, KRAS is targeted by miR-18a. MiR-155and miR-181c target KRAS in twoabnormal networks. Meanwhile, miR-155is present in two abnormal networks, and it hasdifferent regulatory pathways in two abnormal networks. In CML, miR-155targets RHOA,miR-155is regulated by SMAD4, but in AML, miR-155targets FOXO3, FLI1, CSF1R,PODXL, SHIP, MEIS1and CBFB. MiR-155targets KRAS, SPI1and miR-155formfeed-backLoop in two abnormal networks.The abnormal network reveals a part of pathogenesis of four kinds of leukemia fromgenes and miRNAs aspects, every abnormal gene and every abnormal miRNA has disorderexpression mode (‘+’ represents up-regulate,‘-’ represents down-regulate,‘0’ represents noexpression). If these abnormal networks are changed to normal expression network, it will notresult in the occurrence of leukemia. Regulation of abnormal network may be a scheme ongene therapy in leukemia. By comparing the four abnormal networks of leukemia, somecommon regulatory pathways and some typical regulatory pathways were found from genesand miRNAs aspects, it may be a specific scheme on gene therapy in different leukemia.