Background:Despite the success of tyrosine kinase inhibitors in chronic myeloid leukemia(CML)therapy,CML still faces the challenges of drug resistance and progression to blast crisis.Twenty-five percent of patients ha...Background:Despite the success of tyrosine kinase inhibitors in chronic myeloid leukemia(CML)therapy,CML still faces the challenges of drug resistance and progression to blast crisis.Twenty-five percent of patients have imatinib resistance and treatment difficulties due to heterogeneity after progression,but little is known about the mechanism.A key transcription factor in hematopoiesis,MYB,has been reported to increase abnormally in several types of aggressive blood disorders including CML.Methods:This study used a zebrafish model to explore the relationship between BCR/ABL1 and c-myb in CML progression.A CML zebrafish model was crossed with a c-myb hyperactivity transgenic line.Results:It was found that both exogenous BCR/ABL1 and c-myb could up-regulate the expression of neutrophil-related genes.More seriously,neutrophil accumulation was observed when BCR/ABL1 was combined with c-myb overexpression.Further studies showed that c-myb may be one of the downstream targets of BCR/ABL1 and the effect of BCR/ABL1 on neutrophils was c-myb dependent.Taking advantage of this inheritable in vivo model,it was shown that a combination of imatinib and flavopiridol,a cyclin-dependent kinase inhibitor targeting MYB,could more effectively alleviate the aggressive phenotype of the double transgene line.Conclusion:In summary,this study suggests that c-myb acts downstream of BCR/ABL1 and is involved in CML progression and is therefore a risk factor and a valuable target for the treatment of CML progression.The model used in the study could be helpful in high-throughput drug screening in CML transformation.展开更多
BACKGROUND Colon cancer(CC)occurrence and progression are considerably influenced by the tumor microenvironment.However,the exact underlying regulatory mechanisms remain unclear.AIM To investigate immune infiltration-...BACKGROUND Colon cancer(CC)occurrence and progression are considerably influenced by the tumor microenvironment.However,the exact underlying regulatory mechanisms remain unclear.AIM To investigate immune infiltration-related differentially expressed genes(DEGs)in CC and specifically explored the role and potential molecular mechanisms of complement factor I(CFI).METHODS Immune infiltration-associated DEGs were screened for CC using bioinformatics.Quantitative reverse transcription polymerase chain reaction was used to examine hub DEGs expression in the CC cell lines.Stable CFI-knockdown HT29 and HCT116 cell lines were constructed,and the diverse roles of CFI in vitro were assessed using CCK-8,5-ethynyl-2’-deoxyuridine,wound healing,and transwell assays.Hematoxylin and eosin staining and immunohistochemistry staining were employed to evaluate the influence of CFI on the tumorigenesis of CC xenograft models constructed using BALB/c male nude mice.Key proteins associated with glycolysis and the Wnt pathway were measured using western blotting.RESULTS Six key immune infiltration-related DEGs were screened,among which the expression of CFI,complement factor B,lymphoid enhancer binding factor 1,and SRY-related high-mobility-group box 4 was upregulated,whereas that of fatty acid-binding protein 1,and bone morphogenic protein-2 was downregulated.Furthermore,CFI could be used as a diagnostic biomarker for CC.Functionally,CFI silencing inhibited CC cell proliferation,migration,invasion,and tumor growth.Mechanistically,CFI knockdown downregulated the expression of key glycolysis-related proteins(glucose transporter type 1,hexokinase 2,lactate dehydrogenase A,and pyruvate kinase M2)and the Wnt pathway-related proteins(β-catenin and c-Myc).Further investigation indicated that CFI knockdown inhibited glycolysis in CC by blocking the Wnt/β-catenin/c-Myc pathway.CONCLUSION The findings of the present study demonstrate that CFI plays a crucial role in CC development by influencing glycolysis and the Wnt/β-catenin/c-Myc pathway,indicating that it could serve as a promising target for therapeutic intervention in CC.展开更多
基金National Key R&D Program of ChinaGrant/Award Number:2018YFA0801000+5 种基金National Natural Science Foundation of ChinaGrant/Award Number:32170830Natural Science Foundation of Guangdong ProvinceChinaGrant/Award Number:2021A1515010422South China University of Technology。
文摘Background:Despite the success of tyrosine kinase inhibitors in chronic myeloid leukemia(CML)therapy,CML still faces the challenges of drug resistance and progression to blast crisis.Twenty-five percent of patients have imatinib resistance and treatment difficulties due to heterogeneity after progression,but little is known about the mechanism.A key transcription factor in hematopoiesis,MYB,has been reported to increase abnormally in several types of aggressive blood disorders including CML.Methods:This study used a zebrafish model to explore the relationship between BCR/ABL1 and c-myb in CML progression.A CML zebrafish model was crossed with a c-myb hyperactivity transgenic line.Results:It was found that both exogenous BCR/ABL1 and c-myb could up-regulate the expression of neutrophil-related genes.More seriously,neutrophil accumulation was observed when BCR/ABL1 was combined with c-myb overexpression.Further studies showed that c-myb may be one of the downstream targets of BCR/ABL1 and the effect of BCR/ABL1 on neutrophils was c-myb dependent.Taking advantage of this inheritable in vivo model,it was shown that a combination of imatinib and flavopiridol,a cyclin-dependent kinase inhibitor targeting MYB,could more effectively alleviate the aggressive phenotype of the double transgene line.Conclusion:In summary,this study suggests that c-myb acts downstream of BCR/ABL1 and is involved in CML progression and is therefore a risk factor and a valuable target for the treatment of CML progression.The model used in the study could be helpful in high-throughput drug screening in CML transformation.
文摘BACKGROUND Colon cancer(CC)occurrence and progression are considerably influenced by the tumor microenvironment.However,the exact underlying regulatory mechanisms remain unclear.AIM To investigate immune infiltration-related differentially expressed genes(DEGs)in CC and specifically explored the role and potential molecular mechanisms of complement factor I(CFI).METHODS Immune infiltration-associated DEGs were screened for CC using bioinformatics.Quantitative reverse transcription polymerase chain reaction was used to examine hub DEGs expression in the CC cell lines.Stable CFI-knockdown HT29 and HCT116 cell lines were constructed,and the diverse roles of CFI in vitro were assessed using CCK-8,5-ethynyl-2’-deoxyuridine,wound healing,and transwell assays.Hematoxylin and eosin staining and immunohistochemistry staining were employed to evaluate the influence of CFI on the tumorigenesis of CC xenograft models constructed using BALB/c male nude mice.Key proteins associated with glycolysis and the Wnt pathway were measured using western blotting.RESULTS Six key immune infiltration-related DEGs were screened,among which the expression of CFI,complement factor B,lymphoid enhancer binding factor 1,and SRY-related high-mobility-group box 4 was upregulated,whereas that of fatty acid-binding protein 1,and bone morphogenic protein-2 was downregulated.Furthermore,CFI could be used as a diagnostic biomarker for CC.Functionally,CFI silencing inhibited CC cell proliferation,migration,invasion,and tumor growth.Mechanistically,CFI knockdown downregulated the expression of key glycolysis-related proteins(glucose transporter type 1,hexokinase 2,lactate dehydrogenase A,and pyruvate kinase M2)and the Wnt pathway-related proteins(β-catenin and c-Myc).Further investigation indicated that CFI knockdown inhibited glycolysis in CC by blocking the Wnt/β-catenin/c-Myc pathway.CONCLUSION The findings of the present study demonstrate that CFI plays a crucial role in CC development by influencing glycolysis and the Wnt/β-catenin/c-Myc pathway,indicating that it could serve as a promising target for therapeutic intervention in CC.
