Accumulating evidence supports the association of somatic mutations with tumor occurrence and development.We aimed to identify somatic mutations with important implications in hepatocellular carcinoma(HCC)and explore ...Accumulating evidence supports the association of somatic mutations with tumor occurrence and development.We aimed to identify somatic mutations with important implications in hepatocellular carcinoma(HCC)and explore their possible mechanisms.The gene mutation profiles of HCC patients were assessed,and the tumor mutation burden was calculated.Gene mutations closely associated with tumor mutation burden and patient overall survival were identified.In vivo and in vitro experiments were performed to verify the effects of putative genes on proliferation,invasion,drug resistance,and other malignant biological behaviors of tumor cells.Fourteen genes with a high mutation frequency were identified.The mutation status of 12 of these genes was closely related to the mutation burden.Among these 12 genes,LRP1B mutation was closely associated with patient prognosis.Nine genes were associated with immune cell infiltration.The results of in vivo and in vitro experiments showed that the knockdown of LRP1B promotes tumor cell proliferation and migration and enhances the resistance of tumor cells to liposomal doxorubicin.LRP1B could directly bind to NCSTN and affect its protein expression level,thereby regulating the PI3K/AKT pathway.Our mutational analysis revealed complex and orchestrated liposomal alterations linked to doxorubicin resistance that may also render cancers less susceptible to immunotherapy and also provides new treatment alternatives.展开更多
乳腺癌缺失基因2(deleted in breast cancer 2,DBC2)、亮氨酸拉链基序编码基因1 (leucine zipper tumor suppressor 1,LZTS1)和低密度脂蛋白受体相关蛋白1B基因(low density lipoprotein receptor-related protein 1B,LRP1B)是近年来研...乳腺癌缺失基因2(deleted in breast cancer 2,DBC2)、亮氨酸拉链基序编码基因1 (leucine zipper tumor suppressor 1,LZTS1)和低密度脂蛋白受体相关蛋白1B基因(low density lipoprotein receptor-related protein 1B,LRP1B)是近年来研究较热的3种可能的抑癌基因,越来越多的证据显示这几个基因的突变、异常表达或者增强子的甲基化异常等与多种肿瘤的发生有密切关系。对其进一步的研究将对多种肿瘤的预防和治疗大有裨益。展开更多
The mechanism of sphingosine-1-phosphate(S1P)-mediated phagocytosis remains unknown.Here,we found that S1P or FTY720(an analog of S1P)promoted microglial phagocytosis in stroke independent of S1PRs.First,we used compu...The mechanism of sphingosine-1-phosphate(S1P)-mediated phagocytosis remains unknown.Here,we found that S1P or FTY720(an analog of S1P)promoted microglial phagocytosis in stroke independent of S1PRs.First,we used computer simulation of molecular docking to predict that S1P might be a ligand for triggering receptor expressed on myeloid cells 2(TREM2).Next,microscale thermophoresis(MST),surface plasmon resonance(SPR)and liquid chromatography–tandem mass spectrometry(LC–MS/MS)were performed to reveal that S1P was a novel TREM2 ligand.Then,we confirmed the pro-phagocytosis of S1P targeting in Trem2-Dap12 transfected CHO cells and TREM2 knockdown microglia.Point mutation analysis showed that D104 was the critical binding residue.Trem2^(−/−)mice were used to demonstrate the role of S1P-induced phagocytosis targeting on TREM2 in protecting against ischemic brain injury.Finally,further studies revealed that apolipoprotein E(APOE)loaded with S1P was released by microglia and bound to apoptotic neurons via LDL receptor related protein 1B(LRP1B)and thereby induced microglia to phagocytose apoptotic neurons.Overall,the present work reveals for the first time that S1P acts as a novel endogenous ligand of TREM2 to effectively promote microglial phagocytosis.Our findings provide a new lead compound for developing immunomodulator targeting on TREM2.展开更多
基金funded by the National Natural Science Foundation of China(No.81871653)the Natural Science Foundationof Chongqing,China(No.cstc2020jcyjmsxmx0159)+3 种基金Chongqing Science and Health Joint Medical High-end Talent Project(China)(No.2022GDRC012)Science and Technology Research Program of Chongqing Municipal Education Commission(China)(No.KJZDK202100402 and KJQN201900449)CQMU Program for Youth Innovation in Future Medicine(China)(No.W0073)Second Hospital of Shandong University Cultivation Funding(China)(No.2022YP45).
文摘Accumulating evidence supports the association of somatic mutations with tumor occurrence and development.We aimed to identify somatic mutations with important implications in hepatocellular carcinoma(HCC)and explore their possible mechanisms.The gene mutation profiles of HCC patients were assessed,and the tumor mutation burden was calculated.Gene mutations closely associated with tumor mutation burden and patient overall survival were identified.In vivo and in vitro experiments were performed to verify the effects of putative genes on proliferation,invasion,drug resistance,and other malignant biological behaviors of tumor cells.Fourteen genes with a high mutation frequency were identified.The mutation status of 12 of these genes was closely related to the mutation burden.Among these 12 genes,LRP1B mutation was closely associated with patient prognosis.Nine genes were associated with immune cell infiltration.The results of in vivo and in vitro experiments showed that the knockdown of LRP1B promotes tumor cell proliferation and migration and enhances the resistance of tumor cells to liposomal doxorubicin.LRP1B could directly bind to NCSTN and affect its protein expression level,thereby regulating the PI3K/AKT pathway.Our mutational analysis revealed complex and orchestrated liposomal alterations linked to doxorubicin resistance that may also render cancers less susceptible to immunotherapy and also provides new treatment alternatives.
文摘乳腺癌缺失基因2(deleted in breast cancer 2,DBC2)、亮氨酸拉链基序编码基因1 (leucine zipper tumor suppressor 1,LZTS1)和低密度脂蛋白受体相关蛋白1B基因(low density lipoprotein receptor-related protein 1B,LRP1B)是近年来研究较热的3种可能的抑癌基因,越来越多的证据显示这几个基因的突变、异常表达或者增强子的甲基化异常等与多种肿瘤的发生有密切关系。对其进一步的研究将对多种肿瘤的预防和治疗大有裨益。
基金supported by the National Natural Science Foundation of China (Nos.81973301, 82003732 and 81773701)the Medical Research Project of Jiangsu Commission of Health (No.ZDA2020006, China)+3 种基金the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (No.18KJA310004)the Major Project of Nanjing Medical University (No.NMUD2018008, China)the Postgraduate Research and Practice Innovation Program of Jiangsu Province (Nos.KYCX19_1121 and KYCX20_1417, China)Priority Academic Program Development of Jiangsu Higer Education Institutions (China)
文摘The mechanism of sphingosine-1-phosphate(S1P)-mediated phagocytosis remains unknown.Here,we found that S1P or FTY720(an analog of S1P)promoted microglial phagocytosis in stroke independent of S1PRs.First,we used computer simulation of molecular docking to predict that S1P might be a ligand for triggering receptor expressed on myeloid cells 2(TREM2).Next,microscale thermophoresis(MST),surface plasmon resonance(SPR)and liquid chromatography–tandem mass spectrometry(LC–MS/MS)were performed to reveal that S1P was a novel TREM2 ligand.Then,we confirmed the pro-phagocytosis of S1P targeting in Trem2-Dap12 transfected CHO cells and TREM2 knockdown microglia.Point mutation analysis showed that D104 was the critical binding residue.Trem2^(−/−)mice were used to demonstrate the role of S1P-induced phagocytosis targeting on TREM2 in protecting against ischemic brain injury.Finally,further studies revealed that apolipoprotein E(APOE)loaded with S1P was released by microglia and bound to apoptotic neurons via LDL receptor related protein 1B(LRP1B)and thereby induced microglia to phagocytose apoptotic neurons.Overall,the present work reveals for the first time that S1P acts as a novel endogenous ligand of TREM2 to effectively promote microglial phagocytosis.Our findings provide a new lead compound for developing immunomodulator targeting on TREM2.
