Triple-negative breast cancer(TNBC) is the most challenging breast cancer subtype to treat due to the absence of effective targeted therapies. In this study,we demonstrate that elevated expression of microtubule affin...Triple-negative breast cancer(TNBC) is the most challenging breast cancer subtype to treat due to the absence of effective targeted therapies. In this study,we demonstrate that elevated expression of microtubule affinity-regulating kinase 2(MARK2),but not other MARK family members(MARK1,MARK3,and MARK4),correlates with poor prognosis in TNBC patients. Silencing MARK2 impairs TNBC progression via inhibition of mutant p53(mutp53) signaling. In contrast,silencing any of the other three MARKs either enhances or does not affect TNBC cell growth or migration and has no impact on mutp53 expression. Notably,direct knockdown of mutp53 recapitulates the effects of MARK2 ablation in TNBC cells,further supporting a functional linkage. Moreover,ectopic expression of either wild-type(WT) MARK2 or its kinasedead(KD) mutant enhances mutp53 signaling and promotes TNBC progression;however,MARK2 overexpression does not alter wild-type p53(wtp53) expression or cell growth in luminal breast cancer cells. Significant inverse correlations are also observed between the expression levels of MARK2,THBS1,or HBEGF(two direct target genes of mutp53) and both overall and disease-free survival in TNBC patients harboring mut TP53,whereas no such association exists between MARK2 and survival in breast cancer subtypes expressing wt TP53.MARK2 is predominantly localized in the nucleus of TNBC cells,where it interacts with and stabilizes mutp53 through its UBA and Spacer domains. Consistent with this,MARK2-ΔUBA or MARK2-ΔSpacer mutant proteins fail to bind mutp53 or sustain its signaling,thereby acting as dominant-negative inhibitors that suppress TNBC progression. Collectively,our findings indicate that suppressing MARK2 expression,rather than inhibiting its kinase activity,may represent an effective therapeutic strategy for TNBC with mut TP53.展开更多
Background and objective:Hepatic ischemia-reperfusion injury(HIRI)is a key factor leading to complications and poor prognosis after hepatobiliary surgery,but its pathogenesis remains unclear.Hence,it is a very necessa...Background and objective:Hepatic ischemia-reperfusion injury(HIRI)is a key factor leading to complications and poor prognosis after hepatobiliary surgery,but its pathogenesis remains unclear.Hence,it is a very necessary discovery the prevention and treatment methods and pathological mechanism of HIRI.Methods:Our animal experiments indicated that two doses of dogwood alcohol extract(DAX)at 5 g/kg and 2.5 g/kg(crude drug/mouse body mass)could significantly reduce serum alamine aminotransferase(AST)and aspartate aminotransferase(ALT)in HIRI mice.The level of these two transaminases determined the pharmacodynamic effect of DAX on HIRI.Next,we used the results of network pharmacology and transcriptome sequencing to obtain important prevention and cure target genes,and applied molecular docking to simulate receptor and ligand binding.Finally,immunohistochemical method was made use of verifying the results.Results:When the model group vs control group,administration group vs model group,set padj<0.05,|log2FoldChange|>1.0 filter condition,the intersection between the obtained transcriptome sequencing data set and the network pharmacological target was only heparin-binding epidermal growth factor(HBEGF).Then DockThor online software was applied to make loganin and ursolic acid,small molecular compounds contained in DAX,form complexes with HBEGF active sites through hydrogen bonding to interfere with HIRI.Meanwhile,immunohistochemical test results showed that HBEGF expression decreased in the administration group compared with the model group(^(*)P<0.05).Conclusions:DAX interferes with the occurrence and development of HIRI by down-regulating HBEGF.Our experimental results not only highlight the advantages of traditional Chinese medicine in treating difficult diseases,but also provide a reference for clinical exploration of new methods to prevent and treat HIRI.展开更多
基金supported by the National Key Research and Development Program of China (No. 2023YFA1801900)the National Natural Science Foundation of China (Nos. 82125036,82273964,and 82304538)+1 种基金the Jiangsu Provincial Natural Science Fund for Distinguished Young Scholar (No. BK20230042)the Jiangsu Funding Program for Excellent Postdoctoral Talent (No. 2023ZB171)。
文摘Triple-negative breast cancer(TNBC) is the most challenging breast cancer subtype to treat due to the absence of effective targeted therapies. In this study,we demonstrate that elevated expression of microtubule affinity-regulating kinase 2(MARK2),but not other MARK family members(MARK1,MARK3,and MARK4),correlates with poor prognosis in TNBC patients. Silencing MARK2 impairs TNBC progression via inhibition of mutant p53(mutp53) signaling. In contrast,silencing any of the other three MARKs either enhances or does not affect TNBC cell growth or migration and has no impact on mutp53 expression. Notably,direct knockdown of mutp53 recapitulates the effects of MARK2 ablation in TNBC cells,further supporting a functional linkage. Moreover,ectopic expression of either wild-type(WT) MARK2 or its kinasedead(KD) mutant enhances mutp53 signaling and promotes TNBC progression;however,MARK2 overexpression does not alter wild-type p53(wtp53) expression or cell growth in luminal breast cancer cells. Significant inverse correlations are also observed between the expression levels of MARK2,THBS1,or HBEGF(two direct target genes of mutp53) and both overall and disease-free survival in TNBC patients harboring mut TP53,whereas no such association exists between MARK2 and survival in breast cancer subtypes expressing wt TP53.MARK2 is predominantly localized in the nucleus of TNBC cells,where it interacts with and stabilizes mutp53 through its UBA and Spacer domains. Consistent with this,MARK2-ΔUBA or MARK2-ΔSpacer mutant proteins fail to bind mutp53 or sustain its signaling,thereby acting as dominant-negative inhibitors that suppress TNBC progression. Collectively,our findings indicate that suppressing MARK2 expression,rather than inhibiting its kinase activity,may represent an effective therapeutic strategy for TNBC with mut TP53.
基金supported by the Health Commission of Tianjin,China(ZC20215).
文摘Background and objective:Hepatic ischemia-reperfusion injury(HIRI)is a key factor leading to complications and poor prognosis after hepatobiliary surgery,but its pathogenesis remains unclear.Hence,it is a very necessary discovery the prevention and treatment methods and pathological mechanism of HIRI.Methods:Our animal experiments indicated that two doses of dogwood alcohol extract(DAX)at 5 g/kg and 2.5 g/kg(crude drug/mouse body mass)could significantly reduce serum alamine aminotransferase(AST)and aspartate aminotransferase(ALT)in HIRI mice.The level of these two transaminases determined the pharmacodynamic effect of DAX on HIRI.Next,we used the results of network pharmacology and transcriptome sequencing to obtain important prevention and cure target genes,and applied molecular docking to simulate receptor and ligand binding.Finally,immunohistochemical method was made use of verifying the results.Results:When the model group vs control group,administration group vs model group,set padj<0.05,|log2FoldChange|>1.0 filter condition,the intersection between the obtained transcriptome sequencing data set and the network pharmacological target was only heparin-binding epidermal growth factor(HBEGF).Then DockThor online software was applied to make loganin and ursolic acid,small molecular compounds contained in DAX,form complexes with HBEGF active sites through hydrogen bonding to interfere with HIRI.Meanwhile,immunohistochemical test results showed that HBEGF expression decreased in the administration group compared with the model group(^(*)P<0.05).Conclusions:DAX interferes with the occurrence and development of HIRI by down-regulating HBEGF.Our experimental results not only highlight the advantages of traditional Chinese medicine in treating difficult diseases,but also provide a reference for clinical exploration of new methods to prevent and treat HIRI.
