Glioblastoma(GBM)is the most aggressive cancer of the brain and has a high mortality rate due to the lack of effective treatment strategy.Clarification of molecular mechanisms of GBM’s characteristic invasive growth ...Glioblastoma(GBM)is the most aggressive cancer of the brain and has a high mortality rate due to the lack of effective treatment strategy.Clarification of molecular mechanisms of GBM’s characteristic invasive growth is urgently needed to improve the poor prognosis.Single-nuclear sequencing of primary and recurrent GBM samples revealed that levels of M3 muscarinic acetylcholine receptor(CHRM3)were significantly higher in the recurrent samples than in the primary samples.Moreover,immunohistochemical staining of an array of GBM samples showed that high levels of CHRM3 correlated with poor prognosis,consistent with The Cancer Genome Atlas database.Knockdown of CHRM3 inhibited GBM cell growth and invasion.An assay of orthotopic GBM animal model in vivo indicated that inhibition of CHRM3 significantly suppressed GBM progression with prolonged survival time.Transcriptome analysis revealed that CHRM3 knockdown significantly reduced an array of classic factors involved in cancer invasive growth,including MMP1/MMP3/MMP10/MMP12 and CXCL1/CXCL5/CXCL8.Taken together,CHRM3 is a novel and vital factor of GBM progression via regulation of multiple oncogenic genes and may serve as a new biomarker for prognosis and therapy of GBM patients.展开更多
CXCL3 belongs to the CXC-type chemokine family and is known to play a multifaceted role in various human malignancies.While it's clinical significance and mechanisms of action in uterine cervical cancer(UCC)remain...CXCL3 belongs to the CXC-type chemokine family and is known to play a multifaceted role in various human malignancies.While it's clinical significance and mechanisms of action in uterine cervical cancer(UCC)remain unclear.This investigation demonstrated that the UCC cell line HeL.a expressed CXCL3,and strong expression of CXCL3 was detected in UCC tissues relative to nontumor tissues.In addition,CXCL3 expression was strongly correlated with CXCL5 expression in UCC tissues.In vitro,HeLa cells overexpressing CXCL3,HeLa cells treated with exogenous CXCL3 or treated with conditioned medium from WPMY cells overexpresing CXCL3,exhibited enhanced proliferation and migration activities.展开更多
Our study investigated the host cell protein which can interact with SARS-CoV N protein, and explored the functional connections. The eukaryotic expression vectors pEGFP-N1/SARS-CoVN and pdsRed2-N1/ CXCL16 were constr...Our study investigated the host cell protein which can interact with SARS-CoV N protein, and explored the functional connections. The eukaryotic expression vectors pEGFP-N1/SARS-CoVN and pdsRed2-N1/ CXCL16 were constructed and used to co-transfect HEK293FT cells by the calcium phosphate method. The HIS-tagged fusion protein SARS-CoVN-GFP was then built and purified for the binding assay in vitro. The co-localization of SARS-CoVN and CXCL16 in the cytoplasm of HEK293FT cells was also shown using confocal laser scanning microscopy. It is suggested that their interaction might be through direct combination. Under a fluorescence microscope, it was observed that the purified fusion protein SARS-CoVN-GFP was attached to the cell membrane of CXCL16-transfected cells, indicating that SARS-CoVN and CXCL16 can be mutually combined.展开更多
Objective:Colorectal cancer(CRC)is a major cause of cancer-related deaths worldwide.The class of chemokines known as cysteine-x-cysteine(CXC)motif ligands(CXCL)is thought to have a significant role in inflammation.A p...Objective:Colorectal cancer(CRC)is a major cause of cancer-related deaths worldwide.The class of chemokines known as cysteine-x-cysteine(CXC)motif ligands(CXCL)is thought to have a significant role in inflammation.A previous study implicated that CXCL family may play a role in angiogenesis and tumor development.In this comprehensive study,16 CXCLs in CRC will be analyzed for their prognostic values and expression patterns.Methods:To investigate CXCLs expression,immune cell infiltration,prognostic value significance,and genetic alteration among CRC patients,Gene Expression Profiling Interactive Analysis 2(GEPIA2),Kaplan-Meier plotter(K-M plotter),Gene Set Cancer Analysis(GSCA),STRING,GeneMANIA,and Sangerbox3.0 were employed.Results:As a result of our study,there was a significant increase in the levels of CXCL1/2/3/4/5/8/9/10/11/13/14/16 in CRC tissues,whereas CXCL12 was reduced.The expression of CXCL1/2/3/9/10/11 in CRC was linked to tumor stage.High expression of CXCL2/3/14 was associated with longer overall survival(OS)in colon adenocarcinoma(COAD)patients,and the overexpression of CXCL2/6/9/11/13 was related to long OS in rectum adenocarcinoma(READ)patients.Additionally,patients with CRC who expressed high levels of CXCL9/10/11 tended to have a longer disease-free survival(DFS).Furthermore,the functions of differentially expressed CXCLs were mainly involved in cytokine activity and chemokine effects.A significant correlation has been found between CXCLs expression and the infiltration of diverse immune cells in COAD and READ,including six types of CD4+T cells,macrophages,neutrophils,B cells,CD8+T cells,and dendritic cells.Conclusions:According to our study,CXCLs may not only serve as prognostic markers for CRC patients but also affect the immune status of CRC tissues,thereby providing new ideas for immunotherapy.展开更多
Chemokine 12(CXCL12), also known as stromal cell derived factor-1(SDF-1) and a member of the CXC chemokine subfamily, is ubiquitously expressed in many tissues and cell types. It interacts specifically with the ligand...Chemokine 12(CXCL12), also known as stromal cell derived factor-1(SDF-1) and a member of the CXC chemokine subfamily, is ubiquitously expressed in many tissues and cell types. It interacts specifically with the ligand for the transmembrane G protein-coupled receptors CXCR4 and CXCR7. The CXCL12/CXCR4 axis takes part in a series of physiological, biochemical, and pathological process, such as inflammation and leukocyte trafficking, cancer-induced bone pain, and postsurgical pain, and also is a key factor in the cross-talking between tumor cells and their microenvironment. Aberrant overexpression of CXCR4 is critical for tumor survival, proliferation, angiogenesis, homing and metastasis. In this review, we summarized the role of CXCL12/CXCR4 in cancer, CXCR4 inhibitors under clinical study, and natural product CXCR4 antagonists. In conclusion, the CXCL12/CXCR4 signaling is important for tumor development and targeting the pathway might represent an effective approach to developing novel therapy in cancer treatment.Chemokine 12(CXCL12), also known as stromal cell derived factor-1(SDF-1) and a member of the CXC chemokine subfamily, is ubiquitously expressed in many tissues and cell types. It interacts specifically with the ligand for the transmembrane G protein-coupled receptors CXCR4 and CXCR7. The CXCL12/CXCR4 axis takes part in a series of physiological, biochemical, and pathological process, such as inflammation and leukocyte trafficking, cancer-induced bone pain, and postsurgical pain, and also is a key factor in the cross-talking between tumor cells and their microenvironment. Aberrant overexpression of CXCR4 is critical for tumor survival, proliferation, angiogenesis, homing and metastasis. In this review, we summarized the role of CXCL12/CXCR4 in cancer, CXCR4 inhibitors under clinical study, and natural product CXCR4 antagonists. In conclusion, the CXCL12/CXCR4 signaling is important for tumor development and targeting the pathway might represent an effective approach to developing novel therapy in cancer tr展开更多
The CXC chemokine CXCL12 is an important factor in physiological and pathological processes, includingembryogenesis, hematopoiesis, angiogenesis and inflammation, because it activates and/or induces migration ofhemato...The CXC chemokine CXCL12 is an important factor in physiological and pathological processes, includingembryogenesis, hematopoiesis, angiogenesis and inflammation, because it activates and/or induces migration ofhematopoietic progenitor and stem cells, endothelial cells and most leukocytes. Therefore, CXCL12 activity istightly regulated at multiple levels. CXCL12 has the unique property of existing in six splice variants in humans,each having a specific tissue distribution and in vivo activity. Controlled splice variant transcription and mRNAstability determine the CXCL12 expression profile. CXCL12 fulfills its functions in homeostatic and pathologicalconditions by interacting with its receptors CXC chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3(ACKR3) and by binding to glycosaminoglycans (GAGs) in tissues and on the endothelium to allow a properpresentation to passing leukocytes. Homodimerizaton and heterodimerization of CXCL12 and its receptors can altertheir signaling activity, as exemplified by the synergy between CXCL12 and other chemokines in leukocyte migrationassays. Receptor binding may also initiate CXCL12 internalization and its subsequent removal from theenvironment. Furthermore, CXCL12 activity is regulated by posttranslational modifications. Proteolytic removal ofNH2- or COOH-terminal amino acids, citrullination of arginine residues by peptidyl arginine deiminases or nitrationof tyrosine residues reduce CXCL12 activity. This review summarizes the interactions of CXCL12 with the cellularenvironment and discusses the different levels of CXCL12 activity regulation.展开更多
Chemokines are involved in human hepatocellular carcinoma （HCC） carcinogenesis. However, the exact mechanism of chemokines in HCC carcinogenesis remains unknown. Here we investigated the roles of chemokine receptor...Chemokines are involved in human hepatocellular carcinoma （HCC） carcinogenesis. However, the exact mechanism of chemokines in HCC carcinogenesis remains unknown. Here we investigated the roles of chemokine receptor 4 （CXCR4） and chemokine ligand 12 （CXCL12） in the metastasis of HCC. We found that the expression levels of CXCR4 mRNA in HCC tissues, MHCC97 cells, and HUVEC cells were 2.52 ±1.13, 2.34 ±1.16 and 1.63 ±1.26, respectively and that the CXCR4 protein levels were 1.38 ± 0.13, 1.96± 0.32 and 1.86 ±0.21, respectively. In contrast, CXCR4 was not detected in normal hepatic tissues. In 78 HCC patients, we also found that the concentration of CXCL12 in cancerous ascitic fluid was 783-8,364 pg/ml and that CXCL12 mRNA level in HCC metastasis portal lymph nodes was 1.21 ± 0.87 but undetectable in normal hepatic tissues. Finally we discovered that recombinant human CXCL12 could induce MHCC97 cells and HUVEC cells to migrate with chemotactic indexes （CI） of 3.9 ±1.1 and 4.1± 1.6, respectively. Cancerous ascitic fluid could also induce the migration of MHCC97 cells with a CI of 1.9 ± 0.8. Thus, our data suggest that CXCR4 and CXCL12 may play an important role in the metastasis of HCC by promoting the migration of tumor cells.展开更多
AIM： To evaluate the expression of C-X-C motif chemokine receptor 4 （CXCR4） and its signaling cascades, which were previously identified as a key factor for cancer cell progression and metastasis, in cholangiocarci...AIM： To evaluate the expression of C-X-C motif chemokine receptor 4 （CXCR4） and its signaling cascades, which were previously identified as a key factor for cancer cell progression and metastasis, in cholangiocarcinoma cell lines. METHODS： The expression of CXCR4 and its signaling cascades were determined in the cholangiocarcinoma cell lines （RMCCA1 and KKU100） by Western blotting. The invasion assays and the detection of actin polymerization were tested in these cholangiocarcinoma cells treated with CXC chemokine ligand -12 （CXCL12）. RESULTS： Expression of CXCR4 was detected in both cholangiocarcinoma cell lines and activation of CXCR4 with CXCL12 triggered the signaling via the extracellular signal-regulated kinase-1/2 （ERK1/2） and phosphoinositide 3-kinase （PI3K） and induction of cholangiocarcinoma cell invasion, and displayed high levels of actin polymerization. Addition of CXCR4 inhibitor （AMD3100） abrogated CXCL12-induced phosphorylation of MEKI/2 and Akt in these cells. Moreover, treatment with MEK1/2 inhibitor （U0126） or PI3K inhibitor （LY294002） also attenuated the effect of CXCL12- induced cholangiocarcinoma cell invasion. CONCLUSION： These results indicated that the activation of CXCR4 and its signaling pathways （MEK1/2 and Akt） are essential for CXCL12-induced cholangiocarcinoma cell invasion. This rises Implications on a potential role for the inhibition of CXCR4 or its signal cascades in the treatment of cholangiocarcinoma.展开更多
基金supported by Research Fund for Academician Lin He New Medicine(JYHL2021FMS14)Shandong Provincial Natural Science Foundation(ZR2021QH337)PhD Fund of Affiliated Hospital of Jining Medical University(2021-BS-002).
文摘Glioblastoma(GBM)is the most aggressive cancer of the brain and has a high mortality rate due to the lack of effective treatment strategy.Clarification of molecular mechanisms of GBM’s characteristic invasive growth is urgently needed to improve the poor prognosis.Single-nuclear sequencing of primary and recurrent GBM samples revealed that levels of M3 muscarinic acetylcholine receptor(CHRM3)were significantly higher in the recurrent samples than in the primary samples.Moreover,immunohistochemical staining of an array of GBM samples showed that high levels of CHRM3 correlated with poor prognosis,consistent with The Cancer Genome Atlas database.Knockdown of CHRM3 inhibited GBM cell growth and invasion.An assay of orthotopic GBM animal model in vivo indicated that inhibition of CHRM3 significantly suppressed GBM progression with prolonged survival time.Transcriptome analysis revealed that CHRM3 knockdown significantly reduced an array of classic factors involved in cancer invasive growth,including MMP1/MMP3/MMP10/MMP12 and CXCL1/CXCL5/CXCL8.Taken together,CHRM3 is a novel and vital factor of GBM progression via regulation of multiple oncogenic genes and may serve as a new biomarker for prognosis and therapy of GBM patients.
文摘CXCL3 belongs to the CXC-type chemokine family and is known to play a multifaceted role in various human malignancies.While it's clinical significance and mechanisms of action in uterine cervical cancer(UCC)remain unclear.This investigation demonstrated that the UCC cell line HeL.a expressed CXCL3,and strong expression of CXCL3 was detected in UCC tissues relative to nontumor tissues.In addition,CXCL3 expression was strongly correlated with CXCL5 expression in UCC tissues.In vitro,HeLa cells overexpressing CXCL3,HeLa cells treated with exogenous CXCL3 or treated with conditioned medium from WPMY cells overexpresing CXCL3,exhibited enhanced proliferation and migration activities.
文摘Our study investigated the host cell protein which can interact with SARS-CoV N protein, and explored the functional connections. The eukaryotic expression vectors pEGFP-N1/SARS-CoVN and pdsRed2-N1/ CXCL16 were constructed and used to co-transfect HEK293FT cells by the calcium phosphate method. The HIS-tagged fusion protein SARS-CoVN-GFP was then built and purified for the binding assay in vitro. The co-localization of SARS-CoVN and CXCL16 in the cytoplasm of HEK293FT cells was also shown using confocal laser scanning microscopy. It is suggested that their interaction might be through direct combination. Under a fluorescence microscope, it was observed that the purified fusion protein SARS-CoVN-GFP was attached to the cell membrane of CXCL16-transfected cells, indicating that SARS-CoVN and CXCL16 can be mutually combined.
文摘Objective:Colorectal cancer(CRC)is a major cause of cancer-related deaths worldwide.The class of chemokines known as cysteine-x-cysteine(CXC)motif ligands(CXCL)is thought to have a significant role in inflammation.A previous study implicated that CXCL family may play a role in angiogenesis and tumor development.In this comprehensive study,16 CXCLs in CRC will be analyzed for their prognostic values and expression patterns.Methods:To investigate CXCLs expression,immune cell infiltration,prognostic value significance,and genetic alteration among CRC patients,Gene Expression Profiling Interactive Analysis 2(GEPIA2),Kaplan-Meier plotter(K-M plotter),Gene Set Cancer Analysis(GSCA),STRING,GeneMANIA,and Sangerbox3.0 were employed.Results:As a result of our study,there was a significant increase in the levels of CXCL1/2/3/4/5/8/9/10/11/13/14/16 in CRC tissues,whereas CXCL12 was reduced.The expression of CXCL1/2/3/9/10/11 in CRC was linked to tumor stage.High expression of CXCL2/3/14 was associated with longer overall survival(OS)in colon adenocarcinoma(COAD)patients,and the overexpression of CXCL2/6/9/11/13 was related to long OS in rectum adenocarcinoma(READ)patients.Additionally,patients with CRC who expressed high levels of CXCL9/10/11 tended to have a longer disease-free survival(DFS).Furthermore,the functions of differentially expressed CXCLs were mainly involved in cytokine activity and chemokine effects.A significant correlation has been found between CXCLs expression and the infiltration of diverse immune cells in COAD and READ,including six types of CD4+T cells,macrophages,neutrophils,B cells,CD8+T cells,and dendritic cells.Conclusions:According to our study,CXCLs may not only serve as prognostic markers for CRC patients but also affect the immune status of CRC tissues,thereby providing new ideas for immunotherapy.
基金supported by the National Natural Science Foundation of China(Nos.81773774,81473231,and 81673461)Science Foundation for Distinguished Young Scholars of Jiangsu Province(No.BK20150028)+3 种基金the National Science and Technology Major Project(No.2017ZX09301014)the Project Program of State Key Laboratory of Natural Medicines,China Pharmaceutical University(No.SKLNMZZCX201823)Program for Changjiang Scholars and Innovative Research Team in University(No.IRT1193)the Open Project of State Key Laboratory Cultivation Base for TCM Quality and Efficacy,Nanjing University of Chinese Medicine(No.TCMQ&E201704)
文摘Chemokine 12(CXCL12), also known as stromal cell derived factor-1(SDF-1) and a member of the CXC chemokine subfamily, is ubiquitously expressed in many tissues and cell types. It interacts specifically with the ligand for the transmembrane G protein-coupled receptors CXCR4 and CXCR7. The CXCL12/CXCR4 axis takes part in a series of physiological, biochemical, and pathological process, such as inflammation and leukocyte trafficking, cancer-induced bone pain, and postsurgical pain, and also is a key factor in the cross-talking between tumor cells and their microenvironment. Aberrant overexpression of CXCR4 is critical for tumor survival, proliferation, angiogenesis, homing and metastasis. In this review, we summarized the role of CXCL12/CXCR4 in cancer, CXCR4 inhibitors under clinical study, and natural product CXCR4 antagonists. In conclusion, the CXCL12/CXCR4 signaling is important for tumor development and targeting the pathway might represent an effective approach to developing novel therapy in cancer treatment.Chemokine 12(CXCL12), also known as stromal cell derived factor-1(SDF-1) and a member of the CXC chemokine subfamily, is ubiquitously expressed in many tissues and cell types. It interacts specifically with the ligand for the transmembrane G protein-coupled receptors CXCR4 and CXCR7. The CXCL12/CXCR4 axis takes part in a series of physiological, biochemical, and pathological process, such as inflammation and leukocyte trafficking, cancer-induced bone pain, and postsurgical pain, and also is a key factor in the cross-talking between tumor cells and their microenvironment. Aberrant overexpression of CXCR4 is critical for tumor survival, proliferation, angiogenesis, homing and metastasis. In this review, we summarized the role of CXCL12/CXCR4 in cancer, CXCR4 inhibitors under clinical study, and natural product CXCR4 antagonists. In conclusion, the CXCL12/CXCR4 signaling is important for tumor development and targeting the pathway might represent an effective approach to developing novel therapy in cancer tr
基金This research was supported by the Interuniversity Attraction Poles Programme initiated by the Belgian Science Policy Office(I.A.P.Project 7/40)the Fund for Scientific Research of Flanders(FWOVlaanderen Projects G.0D25.17N,G.0764.14,and G.0D66.13)+1 种基金the Concerted Research Actions of the Regional Government of Flanders(GOA/12/017)C1 funding(C16/17/010)of KU Leuven.
文摘The CXC chemokine CXCL12 is an important factor in physiological and pathological processes, includingembryogenesis, hematopoiesis, angiogenesis and inflammation, because it activates and/or induces migration ofhematopoietic progenitor and stem cells, endothelial cells and most leukocytes. Therefore, CXCL12 activity istightly regulated at multiple levels. CXCL12 has the unique property of existing in six splice variants in humans,each having a specific tissue distribution and in vivo activity. Controlled splice variant transcription and mRNAstability determine the CXCL12 expression profile. CXCL12 fulfills its functions in homeostatic and pathologicalconditions by interacting with its receptors CXC chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3(ACKR3) and by binding to glycosaminoglycans (GAGs) in tissues and on the endothelium to allow a properpresentation to passing leukocytes. Homodimerizaton and heterodimerization of CXCL12 and its receptors can altertheir signaling activity, as exemplified by the synergy between CXCL12 and other chemokines in leukocyte migrationassays. Receptor binding may also initiate CXCL12 internalization and its subsequent removal from theenvironment. Furthermore, CXCL12 activity is regulated by posttranslational modifications. Proteolytic removal ofNH2- or COOH-terminal amino acids, citrullination of arginine residues by peptidyl arginine deiminases or nitrationof tyrosine residues reduce CXCL12 activity. This review summarizes the interactions of CXCL12 with the cellularenvironment and discusses the different levels of CXCL12 activity regulation.
文摘Chemokines are involved in human hepatocellular carcinoma （HCC） carcinogenesis. However, the exact mechanism of chemokines in HCC carcinogenesis remains unknown. Here we investigated the roles of chemokine receptor 4 （CXCR4） and chemokine ligand 12 （CXCL12） in the metastasis of HCC. We found that the expression levels of CXCR4 mRNA in HCC tissues, MHCC97 cells, and HUVEC cells were 2.52 ±1.13, 2.34 ±1.16 and 1.63 ±1.26, respectively and that the CXCR4 protein levels were 1.38 ± 0.13, 1.96± 0.32 and 1.86 ±0.21, respectively. In contrast, CXCR4 was not detected in normal hepatic tissues. In 78 HCC patients, we also found that the concentration of CXCL12 in cancerous ascitic fluid was 783-8,364 pg/ml and that CXCL12 mRNA level in HCC metastasis portal lymph nodes was 1.21 ± 0.87 but undetectable in normal hepatic tissues. Finally we discovered that recombinant human CXCL12 could induce MHCC97 cells and HUVEC cells to migrate with chemotactic indexes （CI） of 3.9 ±1.1 and 4.1± 1.6, respectively. Cancerous ascitic fluid could also induce the migration of MHCC97 cells with a CI of 1.9 ± 0.8. Thus, our data suggest that CXCR4 and CXCL12 may play an important role in the metastasis of HCC by promoting the migration of tumor cells.
基金Supported by the Grant from National Center for Genetic Engineering and Biotechnology,Thailand and Rajavithi HospitalFund
文摘AIM： To evaluate the expression of C-X-C motif chemokine receptor 4 （CXCR4） and its signaling cascades, which were previously identified as a key factor for cancer cell progression and metastasis, in cholangiocarcinoma cell lines. METHODS： The expression of CXCR4 and its signaling cascades were determined in the cholangiocarcinoma cell lines （RMCCA1 and KKU100） by Western blotting. The invasion assays and the detection of actin polymerization were tested in these cholangiocarcinoma cells treated with CXC chemokine ligand -12 （CXCL12）. RESULTS： Expression of CXCR4 was detected in both cholangiocarcinoma cell lines and activation of CXCR4 with CXCL12 triggered the signaling via the extracellular signal-regulated kinase-1/2 （ERK1/2） and phosphoinositide 3-kinase （PI3K） and induction of cholangiocarcinoma cell invasion, and displayed high levels of actin polymerization. Addition of CXCR4 inhibitor （AMD3100） abrogated CXCL12-induced phosphorylation of MEKI/2 and Akt in these cells. Moreover, treatment with MEK1/2 inhibitor （U0126） or PI3K inhibitor （LY294002） also attenuated the effect of CXCL12- induced cholangiocarcinoma cell invasion. CONCLUSION： These results indicated that the activation of CXCR4 and its signaling pathways （MEK1/2 and Akt） are essential for CXCL12-induced cholangiocarcinoma cell invasion. This rises Implications on a potential role for the inhibition of CXCR4 or its signal cascades in the treatment of cholangiocarcinoma.
