Background:Increased Galectin 3-binding protein(LGALS3BP)serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma(HCC).Considering the crucial role of transforming gro...Background:Increased Galectin 3-binding protein(LGALS3BP)serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma(HCC).Considering the crucial role of transforming growth factor-β1(TGF-β1)in the emergence of these diseases,the present study tested the hypothesis that LGALS3BP regulates the TGF-β1 signaling pathway.Methods:The expression levels of LGALS3BP and TGFB1 were analyzed in patients with metabolic dysfunction-associated steatohepatitis(MASH)and HCC.Multiple omics techniques,such as RNA-sequencing,transposaseaccessible chromatin-sequencing assay,and liquid chromatography-tandem mass spectrometry proteomics,were used to identify the regulatory mechanisms for the LGALS3BP-TGF-β1 axis.The effects of altered TGF-β1 signaling by LGALS3BP were investigated in conditional LGALS3BP-knockin and LGALS3BP-knockout mice.Results:In patients with MASH and HCC,the levels of LGALS3BP and TGFB1 exhibited positive correlations.Stimulation of LGALS3BP by the inflammatory cytokine interferonαin HCC cells or ectopic overexpression of LGALS3BP in hepatocytes promoted the expression levels of TGFB1.Aggravated fibrosis was observed in the livers of hepatocyte-specific LGALS3BP-knockin mice,with increased TGFB1 levels.LGALS3BP directly bound to and assembled integrinαV,an integral mediator required for releasing active TGF-β1 from extracellular latent complex with the rearranged F-actin cytoskeleton.The released TGF-β1 activated JunB transcription factor,which in turn promoted the TGF-β1 positive feedback loop.LGALS3BP deletion in the hepatocytes downregulated TGF-β1 signaling and CCl4 induced fibrosis.Moreover,LGALS3BP depletion hindered hepatocarcinogenesis by limiting the availability of fibrogenic TGF-β1.Conclusion:LGALS3BP plays a crucial role in hepatic fibrosis and carcinogenesis by controlling the TGF-β1 signaling pathway,making it a promising therapeutic target in TGF-β1-related diseases.展开更多
Uveal melanoma(UM)poses a significant lethality,with approximately 50%of those developing metastases surviving less than one year.In the progression of UM,vasculogenic mimicry(VM)induced by hypoxia plays a pivotal rol...Uveal melanoma(UM)poses a significant lethality,with approximately 50%of those developing metastases surviving less than one year.In the progression of UM,vasculogenic mimicry(VM)induced by hypoxia plays a pivotal role,which also partially explains the resistance of UM to anti-angiogenic therapies.Nevertheless,the crucial molecular mechanisms underlying VM in the progres-sion of UM remain unclear.We identified ubiquitin conjugating enzyme E2 G2(UBE2G2)as a critical suppressor through transcriptomic sequencing and metastasis correlation screening.In UM,hypoxia-induced VM and metastasis are markedly exacerbated by UBE2G2 knockdown and significantly allevi-ated by its overexpression.Mechanistically,UBE2G2 directly binds to galectin 3 binding protein(LGALS3BP)and forms a complex with the E3 ubiquitin ligase tripartite motif containing 38(TRIM38),facilitating ubiquitination-mediated degradation of LGALS3BP at the K104 residue.Further-more,UBE2G2 inhibits oncogenic phenotypes by inactivating intracellular PI3K/AKT signaling and re-programming the tumor microenvironment.Therefore,targeting intercellular and intracellular molecular mechanisms of the hypoxiaeUBE2G2eLGALS3BP axis may contribute to developing various therapeu-tic strategies for UM.展开更多
AIM: To determine the efficacy of Mac-2 binding protein (Mac-2bp) for diagnosis of chronic pancreatitis.METHODS: Fifty-nine healthy volunteers (HV), 162 patients with chronic pancreatitis (CP), and 94 patients with pa...AIM: To determine the efficacy of Mac-2 binding protein (Mac-2bp) for diagnosis of chronic pancreatitis.METHODS: Fifty-nine healthy volunteers (HV), 162 patients with chronic pancreatitis (CP), and 94 patients with pancreatic ductal adenocarcinoma (PDAC) were enrolled in this study. We measured serum Mac-2bp using our developed enzyme-linked immunosorbent assay kit. Additional biochemical variables were measured using an automated analyzer (including aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, triglyceride, C-reactive protein, and amylase levels) or chemiluminescent enzyme immunoassay (carbohydrate antigen 19-9 and carcinoembryonic antigen). The ability of Mac-2bp to predict CP diagnosis accurately was assessed using receiver operating characteristic (ROC) analyses.RESULTS: Serum Mac-2bp levels were significantly increased in CP patients compared to HV (P < 0.0001) and PDAC patients (P < 0.0001). Area under the ROC curve values of Mac-2bp for the discrimination of CP from HV and PDAC were 0.727 and 0.784, respectively. Multivariate analyses demonstrated that serum Mac-2bp levels were independent determinants for CP diagnosis from HV and PDAC patients. Immunohistological staining showed that Mac-2bp was expressed faintly in the pancreas tissues of both CP and PDAC patients. Serum aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, and triglyceride levels were significantly higher in patients with CP or PDAC. Serum Mac-2bp levels were highly correlated with protein levels of alanine aminotransferase, γ-glutamyltransferase, and C-reactive protein, but not amylase, suggesting that the damaged liver produces Mac-2bp.CONCLUSION: Measurement of serum Mac-2bp may be a novel and useful biomarker for CP diagnosis as well as liver fibrosis in the general population.展开更多
基金Bio&Medical Technology Development Program of the National Research Foundation,Grant/Award Numbers:NRF-2020M3A9G3080281,NRF-2020R1A5A2031185Korean Government。
文摘Background:Increased Galectin 3-binding protein(LGALS3BP)serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma(HCC).Considering the crucial role of transforming growth factor-β1(TGF-β1)in the emergence of these diseases,the present study tested the hypothesis that LGALS3BP regulates the TGF-β1 signaling pathway.Methods:The expression levels of LGALS3BP and TGFB1 were analyzed in patients with metabolic dysfunction-associated steatohepatitis(MASH)and HCC.Multiple omics techniques,such as RNA-sequencing,transposaseaccessible chromatin-sequencing assay,and liquid chromatography-tandem mass spectrometry proteomics,were used to identify the regulatory mechanisms for the LGALS3BP-TGF-β1 axis.The effects of altered TGF-β1 signaling by LGALS3BP were investigated in conditional LGALS3BP-knockin and LGALS3BP-knockout mice.Results:In patients with MASH and HCC,the levels of LGALS3BP and TGFB1 exhibited positive correlations.Stimulation of LGALS3BP by the inflammatory cytokine interferonαin HCC cells or ectopic overexpression of LGALS3BP in hepatocytes promoted the expression levels of TGFB1.Aggravated fibrosis was observed in the livers of hepatocyte-specific LGALS3BP-knockin mice,with increased TGFB1 levels.LGALS3BP directly bound to and assembled integrinαV,an integral mediator required for releasing active TGF-β1 from extracellular latent complex with the rearranged F-actin cytoskeleton.The released TGF-β1 activated JunB transcription factor,which in turn promoted the TGF-β1 positive feedback loop.LGALS3BP deletion in the hepatocytes downregulated TGF-β1 signaling and CCl4 induced fibrosis.Moreover,LGALS3BP depletion hindered hepatocarcinogenesis by limiting the availability of fibrogenic TGF-β1.Conclusion:LGALS3BP plays a crucial role in hepatic fibrosis and carcinogenesis by controlling the TGF-β1 signaling pathway,making it a promising therapeutic target in TGF-β1-related diseases.
基金supported by the National Natural Science Foundation of China(Nos.82273159 and 82171838)the Jiangsu Province’s Science and Technology Project(No.BE2020722,China).
文摘Uveal melanoma(UM)poses a significant lethality,with approximately 50%of those developing metastases surviving less than one year.In the progression of UM,vasculogenic mimicry(VM)induced by hypoxia plays a pivotal role,which also partially explains the resistance of UM to anti-angiogenic therapies.Nevertheless,the crucial molecular mechanisms underlying VM in the progres-sion of UM remain unclear.We identified ubiquitin conjugating enzyme E2 G2(UBE2G2)as a critical suppressor through transcriptomic sequencing and metastasis correlation screening.In UM,hypoxia-induced VM and metastasis are markedly exacerbated by UBE2G2 knockdown and significantly allevi-ated by its overexpression.Mechanistically,UBE2G2 directly binds to galectin 3 binding protein(LGALS3BP)and forms a complex with the E3 ubiquitin ligase tripartite motif containing 38(TRIM38),facilitating ubiquitination-mediated degradation of LGALS3BP at the K104 residue.Further-more,UBE2G2 inhibits oncogenic phenotypes by inactivating intracellular PI3K/AKT signaling and re-programming the tumor microenvironment.Therefore,targeting intercellular and intracellular molecular mechanisms of the hypoxiaeUBE2G2eLGALS3BP axis may contribute to developing various therapeu-tic strategies for UM.
基金Supported by Grants-in-Aid for Scientific Research (B), No. 15H04810 from the Japan Society for the Promotion of Science, Japanese Society of Laboratory Medicine Fund for the Promotion of Scientific Research, Foundation for Total Health Promotionsupported as a research program from the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct), Ministry of Education, Culture, Sports, Science and Technology of Japan
文摘AIM: To determine the efficacy of Mac-2 binding protein (Mac-2bp) for diagnosis of chronic pancreatitis.METHODS: Fifty-nine healthy volunteers (HV), 162 patients with chronic pancreatitis (CP), and 94 patients with pancreatic ductal adenocarcinoma (PDAC) were enrolled in this study. We measured serum Mac-2bp using our developed enzyme-linked immunosorbent assay kit. Additional biochemical variables were measured using an automated analyzer (including aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, triglyceride, C-reactive protein, and amylase levels) or chemiluminescent enzyme immunoassay (carbohydrate antigen 19-9 and carcinoembryonic antigen). The ability of Mac-2bp to predict CP diagnosis accurately was assessed using receiver operating characteristic (ROC) analyses.RESULTS: Serum Mac-2bp levels were significantly increased in CP patients compared to HV (P < 0.0001) and PDAC patients (P < 0.0001). Area under the ROC curve values of Mac-2bp for the discrimination of CP from HV and PDAC were 0.727 and 0.784, respectively. Multivariate analyses demonstrated that serum Mac-2bp levels were independent determinants for CP diagnosis from HV and PDAC patients. Immunohistological staining showed that Mac-2bp was expressed faintly in the pancreas tissues of both CP and PDAC patients. Serum aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, and triglyceride levels were significantly higher in patients with CP or PDAC. Serum Mac-2bp levels were highly correlated with protein levels of alanine aminotransferase, γ-glutamyltransferase, and C-reactive protein, but not amylase, suggesting that the damaged liver produces Mac-2bp.CONCLUSION: Measurement of serum Mac-2bp may be a novel and useful biomarker for CP diagnosis as well as liver fibrosis in the general population.
