Major gaps in understanding the molecular mechanisms of colorectal cancer(CRC)progression and intestinal mucosal repair have hampered therapeutic development for gastrointestinal disorders.Trefoil factor 3(TFF3)has be...Major gaps in understanding the molecular mechanisms of colorectal cancer(CRC)progression and intestinal mucosal repair have hampered therapeutic development for gastrointestinal disorders.Trefoil factor 3(TFF3)has been reported to be involved in CRC progression and intestinal mucosal repair;however,how TFF3 drives tumors to become more aggressive or metastatic and how TFF3 promotes intestinal mucosal repair are still poorly understood.Here,we found that the upregulated TFF3 in CRC predicted a worse overall survival rate.TFF3 deficiency impaired mucosal restitution and adenocarcinogenesis.CD147,a membrane protein,was identified as a binding partner for TFF3.Via binding to CD147,TFF3 enhanced CD147-CD44s interaction,resulting in signal transducer and activator of transcription 3(STAT3)activation and prostaglandin G/H synthase 2(PTGS2)expression,which were indispensable for TFF3-induced migration,proliferation,and invasion.PTGS2-derived PGE2 bound to prostaglandin E2 receptor EP4 subtype(PTGER4)and contributed to TFF3-stimulated CRC progression.Solution NMR studies of the TFF3-CD147 interaction revealed the key residues critical for TFF3 binding and the induction of PTGS2 expression.The ability of TFF3 to enhance mucosal restitution was weakened by a PTGS2 inhibitor.Blockade of TFF3-CD147 signaling using competitive inhibitory antibodies or a PTGS2 inhibitor reduced CRC lung metastasis in mice.Our findings bring strong evidence that CD147 is a novel receptor for TFF3 and PTGS2 signaling is critical for TFF3-induced mucosal restitution and CRC progression,which widens and deepens the understanding of the molecular function of trefoil factors.展开更多
Background:The mechanism underlying colorectal cancer(CRC)initiation and progression remains elusive,and overall survival is far from satisfactory.Previous studies have shown that PDGFA-associated protein 1(PDAP1)is u...Background:The mechanism underlying colorectal cancer(CRC)initiation and progression remains elusive,and overall survival is far from satisfactory.Previous studies have shown that PDGFA-associated protein 1(PDAP1)is upregulated in several cancers including CRC.Here,we aimed to identify the cause and consequence of PDAP1 dysregulation in CRC and evaluate its role as a potential therapeutic target.Methods:Multi-omics data analysis was performed to identify potential key players in CRC initiation and progression.Immunohistochemistry(IHC)staining was applied to determine the expression pattern of PDAP1 in CRC tissues.Pdap1 conditional knockout mice were used to establish colitis and CRC mouse models.RNA sequencing,a phosphoprotein antibody array,western blotting,histological analysis,5-bromo-2′-deoxyuridine(BrdU)incorporation assay,and interactome analysis were applied to identify the underlying mechanisms of PDAP1.A human patient-derived xenograft(PDX)model was used to assess the potential of PDAP1 as a therapeutic target.Results:PDAP1 was identified as a potential key player in CRC development using multi-omics data analysis.PDAP1 was overexpressed in CRC cells and correlated with reduced overall survival.Further investigation showed that PDAP1 was critical for the regulation of cell proliferation,migration,invasion,and metastasis.Significantly,depletion of Pdap1in intestinal epithelial cells impaired mucosal restitution in dextran sulfate sodium salt-induced colitis and inhibited tumor initiation and growth in colitis-associated cancers.Mechanistic studies showed that c-Myc directly transactivated PDAP1,which contributed to the high PDAP1 expression in CRC cells.PDAP1 interacted with the juxtamembrane domain of epidermal growth factor receptor(EGFR)and facilitated EGFRmitogen-activated protein kinase(MAPK)signaling activation,which resulted in FOS-related antigen 1(FRA-1)expression,thereby facilitating CRC progression.Notably,silencing of PDAP1 could hinder the growth of patient-derived xenografts that sustain high PDAP1 levels.Conclusions:PDAP1 facilitates mucosal restitution and carcinogenesis in colitis-associated cancer.c-Myc-driven upregulation of PDAP1 promotes proliferation,migration,invasion,and metastasis of CRC cells via the EGFRMAPK-FRA-1 signaling axis.These findings indicated that PDAP1 inhibition is warranted for CRC patients with PDAP1 overexpression.展开更多
基金This work was supported by the National Key Research and Development Program of China(2018YFA0109000)the National Postdoctoral Program for Innovative Talents(BX20180376)+2 种基金the National Natural Science Foundation of China(31601127,31670757,81602521,31571469,21807088,82022059 and 81572802)the National Science and Technology Major Project(2017ZX10203205-004-002)the Natural Science Foundation of Guangdong Province(2021A1515012488).
文摘Major gaps in understanding the molecular mechanisms of colorectal cancer(CRC)progression and intestinal mucosal repair have hampered therapeutic development for gastrointestinal disorders.Trefoil factor 3(TFF3)has been reported to be involved in CRC progression and intestinal mucosal repair;however,how TFF3 drives tumors to become more aggressive or metastatic and how TFF3 promotes intestinal mucosal repair are still poorly understood.Here,we found that the upregulated TFF3 in CRC predicted a worse overall survival rate.TFF3 deficiency impaired mucosal restitution and adenocarcinogenesis.CD147,a membrane protein,was identified as a binding partner for TFF3.Via binding to CD147,TFF3 enhanced CD147-CD44s interaction,resulting in signal transducer and activator of transcription 3(STAT3)activation and prostaglandin G/H synthase 2(PTGS2)expression,which were indispensable for TFF3-induced migration,proliferation,and invasion.PTGS2-derived PGE2 bound to prostaglandin E2 receptor EP4 subtype(PTGER4)and contributed to TFF3-stimulated CRC progression.Solution NMR studies of the TFF3-CD147 interaction revealed the key residues critical for TFF3 binding and the induction of PTGS2 expression.The ability of TFF3 to enhance mucosal restitution was weakened by a PTGS2 inhibitor.Blockade of TFF3-CD147 signaling using competitive inhibitory antibodies or a PTGS2 inhibitor reduced CRC lung metastasis in mice.Our findings bring strong evidence that CD147 is a novel receptor for TFF3 and PTGS2 signaling is critical for TFF3-induced mucosal restitution and CRC progression,which widens and deepens the understanding of the molecular function of trefoil factors.
基金National Key Research and Development Program of China,Grant/Award Numbers:2018YFA0109000,2019YFC1316303National Postdoctoral Program for Innovative Talents,Grant/Award Number:BX20180376+2 种基金Natural Science Foundation of Shaanxi Province,Grant/Award Number:2020SF-252Basic Research Plan of Natural Science in Shaanxi Province,Grant/Award Number:2020JM-326National Natural Science Foundation of China,Grant/Award Numbers:31601127,82173244。
文摘Background:The mechanism underlying colorectal cancer(CRC)initiation and progression remains elusive,and overall survival is far from satisfactory.Previous studies have shown that PDGFA-associated protein 1(PDAP1)is upregulated in several cancers including CRC.Here,we aimed to identify the cause and consequence of PDAP1 dysregulation in CRC and evaluate its role as a potential therapeutic target.Methods:Multi-omics data analysis was performed to identify potential key players in CRC initiation and progression.Immunohistochemistry(IHC)staining was applied to determine the expression pattern of PDAP1 in CRC tissues.Pdap1 conditional knockout mice were used to establish colitis and CRC mouse models.RNA sequencing,a phosphoprotein antibody array,western blotting,histological analysis,5-bromo-2′-deoxyuridine(BrdU)incorporation assay,and interactome analysis were applied to identify the underlying mechanisms of PDAP1.A human patient-derived xenograft(PDX)model was used to assess the potential of PDAP1 as a therapeutic target.Results:PDAP1 was identified as a potential key player in CRC development using multi-omics data analysis.PDAP1 was overexpressed in CRC cells and correlated with reduced overall survival.Further investigation showed that PDAP1 was critical for the regulation of cell proliferation,migration,invasion,and metastasis.Significantly,depletion of Pdap1in intestinal epithelial cells impaired mucosal restitution in dextran sulfate sodium salt-induced colitis and inhibited tumor initiation and growth in colitis-associated cancers.Mechanistic studies showed that c-Myc directly transactivated PDAP1,which contributed to the high PDAP1 expression in CRC cells.PDAP1 interacted with the juxtamembrane domain of epidermal growth factor receptor(EGFR)and facilitated EGFRmitogen-activated protein kinase(MAPK)signaling activation,which resulted in FOS-related antigen 1(FRA-1)expression,thereby facilitating CRC progression.Notably,silencing of PDAP1 could hinder the growth of patient-derived xenografts that sustain high PDAP1 levels.Conclusions:PDAP1 facilitates mucosal restitution and carcinogenesis in colitis-associated cancer.c-Myc-driven upregulation of PDAP1 promotes proliferation,migration,invasion,and metastasis of CRC cells via the EGFRMAPK-FRA-1 signaling axis.These findings indicated that PDAP1 inhibition is warranted for CRC patients with PDAP1 overexpression.
