Objective:The main reasons for the poor prognoses of pancreatic adenocarcinoma(PA)patients are rapid early-stage progression,advanced stage metastasis,and chemotherapy resistance.Identification of novel diagnostic and...Objective:The main reasons for the poor prognoses of pancreatic adenocarcinoma(PA)patients are rapid early-stage progression,advanced stage metastasis,and chemotherapy resistance.Identification of novel diagnostic and prognostic biomarkers of PA is therefore urgently needed.Methods:Three mRNA microarray datasets were obtained from the Gene Expression Omnibus database to select differentially expressed genes(DEGs).Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses for hub genes were performed using DAVID.Correlations between expression levels of hub genes and cancer-infiltrating immune cells were investigated by TIMER.Cox proportional hazard regression analyses were also performed.Serum hub genes were screened using the HPA platform and verified for diagnostic value using ELISAs.Results:We identified 59 hub genes among 752 DEGs.GO analysis indicated that these 59 hub genes were mainly involved in the defense response to viruses and the type I interferon signaling pathway.We also discovered that RSAD2 and SMC4 were associated with immune cell infiltration in the PA microenvironment.Additionally,DLGAP5 mRNA might be used as an independent risk factor for the prognoses of PA patients.Furthermore,the protein encoded by ISG15,which exists in peripheral blood,was validated as a potential diagnostic biomarker that distinguished PA patients from healthy controls(area under the curve:0.902,95%confidence interval:0.819–0.961).Conclusions:Our study suggested that RSAD2 and SMC4 were associated with immune cell infiltration in the PA microenvironment,while DLGAP5 mRNA expression might be an independent risk factor for the survival prognoses of PA patients.Moreover,ELISAs indicated that serum ISG15 could be a potential novel diagnostic biomarker for PA.展开更多
Understanding the role of neuropilin 2(NRP2)in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone met...Understanding the role of neuropilin 2(NRP2)in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis.We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone.Here,we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis,implicating NRP2 as a promising therapeutic target.Since,osteoclasts present in the tumor microenvironment express NRP2,we have investigated the potential effect of targeting NRP2 in osteoclasts.Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions.Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function.Interestingly,depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone.These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.展开更多
Objective： To investigate the effect ofberbamine on human hepatoma cell line SMMC7721. Methods： The effects of 24 h and 48 h incubation with different concentrations （0-64 μg/ml） of the berbamine on SMMC7721 cell...Objective： To investigate the effect ofberbamine on human hepatoma cell line SMMC7721. Methods： The effects of 24 h and 48 h incubation with different concentrations （0-64 μg/ml） of the berbamine on SMMC7721 cells were evaluated using 3-4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide （MTT） assay. Hoechst 33258 staining was conducted to distinguish the apoptotic cell, and the appearance of sub-G1 stage was determined by PI （propidium iodide） staining, the percentage of apoptotic cell was determined by flow cytometry following annexin V/PI staining. Flow cytometry was performed to analyze the cell cycle distribution and the mitochondrial membrane potential （△ψm）, the expression of activated caspase3 and caspase9 was analyzed by Western-blot. Results： The proliferation of SMMC7721 was decreased after treatment with berbamine in a dose- and time-dependent manner. Berbamine could induce apoptosis in SMMC7721 cells and could cause cell cycle arrest in G0/G1 phase, to induce loss of mitochondrial membrane potential （AVm） and activate caspase3 and caspase9. Berbamine-induced apoptosis could be blocked by the broad caspase inhibitor z-VAD-fmk. Conclusion： Berbamine exerts antiproliferative effects on human hepatocellular carcinoma SMMC7721 cells. The anticancer activity of berbamine could be attributed partly to its inhibition of cell proliferation and induction of apoptosis in cancer cells through loss in mitochondrial transmembrane potential and caspase activation.展开更多
The translocation of YAP from the cytoplasm to the nucleus is critical for its activation and plays a key role in tumor progression.However,the precise molecular mechanisms governing the nuclear import of YAP are not ...The translocation of YAP from the cytoplasm to the nucleus is critical for its activation and plays a key role in tumor progression.However,the precise molecular mechanisms governing the nuclear import of YAP are not fully understood.In this study,we have uncovered a crucial role of SOX9 in the activation of YAP.SOX9 promotes the nuclear translocation of YAP by direct interaction.Importantly,we have identified that the binding between Asp-125 of SOX9 and Arg-124 of YAP is essential for SOX9-YAP interaction and subsequent nuclear entry of YAP.Additionally,we have discovered a novel asymmetrical dimethylation of YAP at Arg-124(YAP-R124me2a)catalyzed by PRMT1.YAP-R124me2a enhances the interaction between YAP and SOX9 and is associated with poor prognosis in multiple cancers.Furthermore,we disrupted the interaction between SOX9 and YAP using a competitive peptide,S-A1,which mimics anα-helix of SOX9 containing Asp-125.S-A1 significantly inhibits YAP nuclear translocation and effectively suppresses tumor growth.This study provides the first evidence of SOX9 as a pivotal regulator driving YAP nuclear translocation and presents a potential therapeutic strategy for YAP-driven human cancers by targeting SOX9-YAP interaction.展开更多
Background This is the inaugural issue of the Journal of the National Cancer Cen-ter(JNCC),a journal designed to appeal to the international commu-nity of health professionals and researchers across the full spectrum ...Background This is the inaugural issue of the Journal of the National Cancer Cen-ter(JNCC),a journal designed to appeal to the international commu-nity of health professionals and researchers across the full spectrum of cancer research.One of its goals is to contribute to cancer research dis-semination and cancer care around the world.We offer this Perspective to emphasize the importance of international collaborations in cancer investigation and in the timely dissemination of research findings.We also describe examples of our own ongoing cross-country collaboration as members of a team of Chinese and U.S.investigators.展开更多
基金supported by grants from the Natural Science Foundation of Tianjin City in China(Grant Nos.18JCYBJC25400 and 18JCZDJC32600)and the National Natural Science Foundation of China(Grant No.81802432).
文摘Objective:The main reasons for the poor prognoses of pancreatic adenocarcinoma(PA)patients are rapid early-stage progression,advanced stage metastasis,and chemotherapy resistance.Identification of novel diagnostic and prognostic biomarkers of PA is therefore urgently needed.Methods:Three mRNA microarray datasets were obtained from the Gene Expression Omnibus database to select differentially expressed genes(DEGs).Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses for hub genes were performed using DAVID.Correlations between expression levels of hub genes and cancer-infiltrating immune cells were investigated by TIMER.Cox proportional hazard regression analyses were also performed.Serum hub genes were screened using the HPA platform and verified for diagnostic value using ELISAs.Results:We identified 59 hub genes among 752 DEGs.GO analysis indicated that these 59 hub genes were mainly involved in the defense response to viruses and the type I interferon signaling pathway.We also discovered that RSAD2 and SMC4 were associated with immune cell infiltration in the PA microenvironment.Additionally,DLGAP5 mRNA might be used as an independent risk factor for the prognoses of PA patients.Furthermore,the protein encoded by ISG15,which exists in peripheral blood,was validated as a potential diagnostic biomarker that distinguished PA patients from healthy controls(area under the curve:0.902,95%confidence interval:0.819–0.961).Conclusions:Our study suggested that RSAD2 and SMC4 were associated with immune cell infiltration in the PA microenvironment,while DLGAP5 mRNA expression might be an independent risk factor for the survival prognoses of PA patients.Moreover,ELISAs indicated that serum ISG15 could be a potential novel diagnostic biomarker for PA.
基金supported by R01 CA 239343-01A1 (K.D.), RO1 CA 182435 (K.D.)Fred and Pamela Buffet cancer center pilot grant (K.D.,2017 & 2018)R21CA241234-01 (S.D.)+4 种基金NE-DHHS-LB506 2020-21 (S.D.) DFG grant (L.C.H. and M.H.M.,project number: 27367690)The Rudolf-Becker-Foundation for translational prostate cancer research (M.H.M.)DFG Schwerpunktprogramm-2084 (L.C.H., μBONE)UO1 CA185148 (S.K.B.)DOD PC170891 (S.K.B.)
文摘Understanding the role of neuropilin 2(NRP2)in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis.We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone.Here,we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis,implicating NRP2 as a promising therapeutic target.Since,osteoclasts present in the tumor microenvironment express NRP2,we have investigated the potential effect of targeting NRP2 in osteoclasts.Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions.Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function.Interestingly,depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone.These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.
基金Project supported by the National Natural Science Foundation of China (No. 30400521)the Science and Technology Department of Zhejiang Province (Nos. 2004D31026 and 2002D3007) the Education Department of Zhejiang Province (No. 20060427), China
文摘Objective： To investigate the effect ofberbamine on human hepatoma cell line SMMC7721. Methods： The effects of 24 h and 48 h incubation with different concentrations （0-64 μg/ml） of the berbamine on SMMC7721 cells were evaluated using 3-4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide （MTT） assay. Hoechst 33258 staining was conducted to distinguish the apoptotic cell, and the appearance of sub-G1 stage was determined by PI （propidium iodide） staining, the percentage of apoptotic cell was determined by flow cytometry following annexin V/PI staining. Flow cytometry was performed to analyze the cell cycle distribution and the mitochondrial membrane potential （△ψm）, the expression of activated caspase3 and caspase9 was analyzed by Western-blot. Results： The proliferation of SMMC7721 was decreased after treatment with berbamine in a dose- and time-dependent manner. Berbamine could induce apoptosis in SMMC7721 cells and could cause cell cycle arrest in G0/G1 phase, to induce loss of mitochondrial membrane potential （AVm） and activate caspase3 and caspase9. Berbamine-induced apoptosis could be blocked by the broad caspase inhibitor z-VAD-fmk. Conclusion： Berbamine exerts antiproliferative effects on human hepatocellular carcinoma SMMC7721 cells. The anticancer activity of berbamine could be attributed partly to its inhibition of cell proliferation and induction of apoptosis in cancer cells through loss in mitochondrial transmembrane potential and caspase activation.
基金supported by the National Natural Science Foundation of China(grant 82072641 to X.Z.,grant 82030021 to W.F.X.,grant 82070620 to H.Q.,grant 81802324 to C.H.D.,grant 81703415 to S.J.C.,grant 91853205 to C.L.,grant 81900514 to K.D.)National Key R&D Program of China(grant 2023YFC2507500 to W.F.X.)+4 种基金the Science and Technology Commission of Shanghai Municipality(grant 21ZR1474700 to S.J.C.)the Youth Innovation Promotion Association of CAS(grant 2022279 to S.J.C.)the High-level New R&D Institute(grant 2019B090904008 to C.L.)High-level Innovative Research Institute(grant 2021B0909050003 to C.L.)This work was also supported by the Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer,and Shanghai Key Laboratory of Hepato-biliary Tumor Biology.
文摘The translocation of YAP from the cytoplasm to the nucleus is critical for its activation and plays a key role in tumor progression.However,the precise molecular mechanisms governing the nuclear import of YAP are not fully understood.In this study,we have uncovered a crucial role of SOX9 in the activation of YAP.SOX9 promotes the nuclear translocation of YAP by direct interaction.Importantly,we have identified that the binding between Asp-125 of SOX9 and Arg-124 of YAP is essential for SOX9-YAP interaction and subsequent nuclear entry of YAP.Additionally,we have discovered a novel asymmetrical dimethylation of YAP at Arg-124(YAP-R124me2a)catalyzed by PRMT1.YAP-R124me2a enhances the interaction between YAP and SOX9 and is associated with poor prognosis in multiple cancers.Furthermore,we disrupted the interaction between SOX9 and YAP using a competitive peptide,S-A1,which mimics anα-helix of SOX9 containing Asp-125.S-A1 significantly inhibits YAP nuclear translocation and effectively suppresses tumor growth.This study provides the first evidence of SOX9 as a pivotal regulator driving YAP nuclear translocation and presents a potential therapeutic strategy for YAP-driven human cancers by targeting SOX9-YAP interaction.
文摘Background This is the inaugural issue of the Journal of the National Cancer Cen-ter(JNCC),a journal designed to appeal to the international commu-nity of health professionals and researchers across the full spectrum of cancer research.One of its goals is to contribute to cancer research dis-semination and cancer care around the world.We offer this Perspective to emphasize the importance of international collaborations in cancer investigation and in the timely dissemination of research findings.We also describe examples of our own ongoing cross-country collaboration as members of a team of Chinese and U.S.investigators.
