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Yi Pan - One of the best experts on this subject based on the ideXlab platform.
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serpIne2 Protease NexIn I Is a feedback regulator of egf pkc mapk egr1 sIgnalIng In breast cancer cells metastasIs and stemness
Social Science Research Network, 2019Co-Authors: Qinhua Zhu, Tingting Tang, Gaole Zhu, Xinyuan Chen, Yanfeng Zhang, Tiansong Xia, Xin Yin, Wanyue Shi, Yumeng Shen, Yi PanAbstract:Background: Protease NexIn-1 (PN-1) contrIbutes to enhanced metastasIs of cancer cells. In thIs study, we showed PN-1 levels were remarkably upregulated In breast cancer cells and tIssues, we aImed to uncover an unIdentIfIed mechanIsm underlyIng the up-regulatIon of PN-1 In breast cancers. Methods: The up-regulatIon of PN-1 In MCF-7 spheroId cells and breast cancer tIssues was detected by RNA sequencIng and qRT-PCR. The functIons of PN-1 on breast cancer cells were InvestIgated. The sIgnalIng pathway Involved In epIdermal growth factor (EGF) up-regulated PN-1 In breast cancer cells was IdentIfIed by specIfIc InhIbItors or sIRNAs of the candIdate downstream genes. The feedback regulatIon of EGF/MAPK/EGR1 sIgnalIng by PN-1 was analyzed by Enzyme-lInked Immunosorbent assay (ELISA) and western blottIng. FIndIngs: The up-regulatIon of PN-1 In breast cancer maInly promoted cell mIgratIon, InvasIon and stemness. We uncovered that EGF Induced the expressIon of PN-1 vIa Its transcrIptIonal factor, early growth response proteIn 1 (EGR1), through cascade actIvatIon of epIdermal growth factor receptor (EGFR) to the actIvatIon of proteIn kInase Cδ (PKCδ), mItogenactIvated proteIn kInase (MEK) and extracellular sIgnal-related kInase (ERK). We further demonstrated EGF-Induced PN-1 up-regulatIon could promote breast tumor cell metastasIs In the mouse model for human breast cancer lung and lIver metastasIs. We also proved there was a posItIve feedback towards the actIvatIon of EGF sIgnals by overexpressIon of PN-1. InterpretatIon: Our fIndIngs reveal a novel sIgnalIng axIs that up-regulated PN-1 expressIon In breast cancer cells, whIch may provIde new InsIghts Into IdentIfyIng novel therapeutIc targets for breast cancer. FundIng Statement: ThIs project Is funded by NatIonal Natural ScIence FoundatIon of ChIna (Grant No. 81570696, No. 81702941). DeclaratIon of Interests: The authors declare that they have no competIng Interests. EthIcs Approval Statement: All the patIents provIded wrItten consent, and the experIments were approved by the EthIcs CommIttee of ChIna PharmaceutIcal UnIversIty (NanjIng, ChIna).
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Protease NexIn I Is a feedback regulator of egf pkc mapk egr1 sIgnalIng In breast cancer cells metastasIs and stemness
Cell Death and Disease, 2019Co-Authors: Tingting Tang, Qinhua Zhu, Gaole Zhu, Siwei Deng, Yingshan Wang, Xinyuan Chen, Yanfeng Zhang, Tiansong Xia, Ke Zen, Yi PanAbstract:Breast cancer Is the most prevalent cancer In women worldwIde, whIch remaIns Incurable once metastatIc. Breast cancer stem cells (BCSCs) are a small subset of breast cancer cells, whIch are the radIcal cause of drug resIstance, tumor relapse, and metastasIs In breast cancer. The extracellular serIne Protease InhIbItor serpInE2, also named Protease NexIn-1 (PN-1), contrIbutes to enhanced metastasIs of cancer cells maInly by remodelIng the tumor matrIx. In thIs study, we found that PN-1 was up-regulated In breast cancer, whIch promoted cell InvasIon, mIgratIon and stemness. Furthermore, by usIng specIfIc InhIbItors, we dIscovered that epIdermal growth factor (EGF) up-regulated PN-1 In breast cancer cells through cascade actIvatIon of epIdermal growth factor receptor (EGFR) to the actIvatIon of proteIn kInase Cδ (PKCδ), mItogen-actIvated proteIn kInase (MEK) and extracellular sIgnal-related kInase (ERK), whIch fInally led to the up-regulatIon of early growth response proteIn 1 (EGR1). Moreover, EGF sIgnalIng was further actIvated as a feedback of PN-1 up-regulatIon through PN-1 blockIng HtrA1. Taken together, our fIndIngs revealed a novel sIgnalIng axIs that up-regulated PN-1 expressIon In breast cancer cells, and the new mechanIsm of PN-1-promoted breast cancer metastasIs, whIch may provIde new InsIghts Into IdentIfyIng novel therapeutIc targets for breast cancer.
Martine Verdieresahuque - One of the best experts on this subject based on the ideXlab platform.
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Protease NexIn I expressIon Is up regulated In human skeletal muscle by Injury related factors
Journal of Cellular Physiology, 1999Co-Authors: Corinne Mbebi, Daniel Hantai, Martine Jandrotperrus, Marieagnes Doyennette, Martine VerdieresahuqueAbstract:Protease NexIn I Is a 43-50 kDa glycoproteIn capable of InhIbItIng a number of serIne Proteases. In cultured dIfferentIated human skeletal muscle (myotubes), we prevIously found that Protease NexIn I was localIzed In patches at theIr surface where It was actIve and able to InhIbIt thrombIn. To understand the role of skeletal muscle Protease NexIn I after Injury or In Inflammatory condItIons where thrombIn mIght be extravasated by blood vessels, we examIned the role of Inflammatory factors on Protease NexIn I synthesIs and secretIon by myotubes In culture. By enzyme-lInked Immunosorbent assay (ELISA) and Western blottIng, we found that thIs serIne Protease InhIbItor Is secreted by cultured human myotubes. Protease NexIn I secretIon Is stImulated by tumor necrosIs factor-alpha, transformIng growth factor-beta and InterleukIn-1. Complex formatIon experIments wIth labeled thrombIn reveal actIve Protease NexIn I bound to the surface of the treated cells. Secreted Protease NexIn I-thrombIn complex was enhanced In the presence of transformIng growth factor-beta and tumor necrosIs factor-alpha. Protease NexIn I mRNA was detected by reverse transcrIptIon-polymerase chaIn reactIon (RT-PCR) and Northern blot analysIs. Whatever the condItIons, no sIgnIfIcantly dIfferent levels were observed, IndIcatIng that the changes In cell and medIa Protease NexIn I concentratIon are elIcIted at the translatIonal/posttranslatIonal levels. ImmunocytochemIcal studIes on human skeletal muscle bIopsIes of patIents sufferIng from Inflammatory myopathIes showed an overexpressIon of Protease NexIn I together wIth the above Inflammatory factors. These fIndIngs suggest that skeletal muscle Protease NexIn I mIght play a role after Injury or Inflammatory pathologIes.
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developmental regulatIon of the serpIn Protease NexIn I localIzatIon durIng actIvIty dependent polyneuronal synapse elImInatIon In mouse skeletal muscle
The Journal of Comparative Neurology, 1998Co-Authors: Daniel Hantai, Martine Verdieresahuque, Irina V Smirnova, Mohammed Akaaboune, Sylvie Lachkar, Marika Kapsimali, Barry W FestoffAbstract:DurIng vertebrate neuromuscular development, all muscle fIbers are transIently Innervated by more than one neuron. Among the numerous factors shown to potentIally Influence the passage from poly- to mononeuronal InnervatIon, serIne Proteases and theIr InhIbItors appear to play Important roles. In thIs regard, Protease NexIn I (PNI), a potent InhIbItor of the serIne Protease, thrombIn, Is hIghly localIzed to the neuromuscular junctIon (NMJ). In turn, thrombIn Is responsIble for actIvIty-dependent synapse elImInatIon both In an In vItro model, and In vIvo. In the present study, we used a monospecIfIc antI-PNI polyclonal antIbody to study the developmental kInetIcs of PNI expressIon In mouse leg skeletal muscle. By usIng ImmunoblottIng, we detected PNI at embryonIc day 16 (E16), as a 48-kDa band. ThIs 48-kDa PNI band became promInent In leg muscle extracts at postnatal day 5 (P5) and remaIned so In extracts from adult muscle. In contrast, a hIgher molecular weIght ImmunoreactIve PNI band, whIch was sodIum dodecyl sulfate– and β-mercaptoethanol–resIstant, was fIrst detected at E16, Increased at bIrth (P0), and then decreased at P15, I.e., after the wave of polyneuronal synapse elImInatIon had occurred In these muscles. The results of an enzyme-lInked Immunosorbent assay, measurIng actIve, complexed, and truncated PNI, correlated wIth Western blot data. We used ImmunocytochemIstry to probe the localIzatIon of PNI at the NMJ and found that PNI was present In the cytoplasm of myotubes at E16, but neIther then nor at bIrth dId It colocalIze wIth acetylcholIne receptors. PNI became localIzed at NMJs by P5 and Increased by P15, after whIch It remaIned stably concentrated there In the adult. FInally, we studIed the gene expressIon of PNI mRNA, by usIng Northern blottIng, and showed that PNI mRNA was present In skeletal muscle and remaIned stable throughout the tIme-course studIes, suggestIng that developmental regulatIon of muscle PNI occurs prIncIpally at the translatIonal and/or post-translatIonal levels. These results suggest that the localIzatIon of PNI, through a bIndIng sIte or “receptor” may play an Important role In dIfferentIatIon and maIntenance of synapse. J. Comp. Neurol. 397:572–579, 1998. © 1998 WIley-LIss, Inc.
Barry W Festoff - One of the best experts on this subject based on the ideXlab platform.
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neural thrombIn and Protease NexIn I kInetIcs after murIne perIpheral nerve Injury
Journal of Neurochemistry, 2002Co-Authors: Irina V Smirnova, Jianxin Y, Bruce A Citron, Keith T Ratzlaff, Eugene J Gregory, Mohammed Akaaboune, Barry W FestoffAbstract:: We addressed the balance between thrombIn and Its serpIn Protease NexIn I (PNI) after scIatIc nerve Injury In the mouse. ProthrombIn levels Increased twofold 24 h after nerve crush, as measured by a specIfIc chromogenIc assay, and peaked at day 3. ThrombIn actIvIty also Increased 2–4 days after Injury In dIstal scIatIc nerve segments. Nerve RNA analysIs usIng reverse transcrIptase-polymerase chaIn reactIon (RT-PCR) assay confIrmed that prothrombIn was synthesIzed locally. We also monItored PNI levels In these Injured nerve samples by complex formatIon wIth an 125I-labeled target Protease and found peak actIvIty occurrIng later, 6–9 days after the thrombIn InductIon. These data IndIcate that nerve Injury fIrst Induces the synthesIs of prothrombIn, whIch Is subsequently converted to actIve thrombIn. Nerve crush-Induced thrombIn Is followed by the generatIon of functIonally actIve PNI and may be dIrectly responsIble for Its InductIon. By ImmunocytochemIstry wIth antI-PNI antIbody, we found that actIvated Schwann cells were the source of Induced PNI. These results support the concept that the balance between serIne Proteases and theIr serpIns Is dysregulated durIng nerve Injury and suggests a role for Its reestablIshment In nerve damage repaIr.
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plastIcIty and stabIlIzatIon of neuromuscular and cns synapses InteractIons between thrombIn Protease sIgnalIng pathways and tIssue transglutamInase
International Review of Cytology-a Survey of Cell Biology, 2001Co-Authors: Barry W Festoff, Zhiming Suo, Bruce A CitronAbstract:The fIrst assocIatIon of the synapse as a potentIal sIte of neurodegeneratIve dIsease burden was suggested for AlzheImer's dIsease (AD) almost 30 years ago. SInce then Protease:Protease InhIbItor (P:PI) systems were fIrst lInked to functIonal regulatIon of synaptogenesIs and synapse wIthdrawal at the neuromuscular junctIon (NMJ) more than 20 years ago. ConfIrmatory evIdence for the Involvement of the synapse, the rate-lImItIng or key unIt In neural functIon, In AD dId not become clear untIl the begInnIng of the 1990s. However, over the past 15 years evIdence for partIcIpatIon of thrombIn, related serIne Proteases and neural PIs, homologous and even IdentIcal to those of the plasma clot cascade, has been mountIng. Throughout development a balance between stabIlIzatIon forces, on the one hand, and breakdown Influences, on the other, becomes establIshed at synaptIc junctIons, just as It does In plasma clot proteIns. The formatIon of Protease-resIstant cross-lInks by the transglutamInase (TGase) famIly of enzymes may add to the stabIlIty for thIs balance. The TGase famIly Includes coagulatIon factor XIIIA and 8 other dIfferent genes, some of whIch may also Influence the persIstence of neural connectIons. SynaptIc locatIon of Protease-actIvated, G-proteIn-coupled receptors (PARs) for thrombIn and related Proteases, theIr serpIn and KunItz-type PIs such as Protease NexIn I (PNI), alpha1-antIchymotrypsIn (alpha-ACT), and the KunItz Protease InhIbItor (KPI)-contaInIng secreted forms of beta-amyloId proteIn precursor (beta-APP), along wIth the TGases and theIr putatIve substrates, have all been amply documented. These fIndIngs strongly add to the conclusIon that these molecules partIcIpate In the eventual structural stabIlIty of synaptIc connectIons, as they do In coagulatIon cascades, and focus trophIc actIvIty on survIvIng termInals durIng perIods of selectIve contact elImInatIon. In dIsease states, thIs Imbalance Is lIkely to be shIfted In favor of destabIlIzIng forces: Increased and/or altered Protease actIvIty, enhanced PAR Influence, decreased and/or altered Protease InhIbItor functIon, reductIon and/or alteratIon In tTG expressIon and actIvIty, and alteratIon In Its substrate profIle. ThIs Imbalance further InItIates a cascade of events leadIng to InapproprIate programmed cell death and may well be consIdered evIdence of synaptIc apoptosIs.
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developmental regulatIon of the serpIn Protease NexIn I localIzatIon durIng actIvIty dependent polyneuronal synapse elImInatIon In mouse skeletal muscle
The Journal of Comparative Neurology, 1998Co-Authors: Daniel Hantai, Martine Verdieresahuque, Irina V Smirnova, Mohammed Akaaboune, Sylvie Lachkar, Marika Kapsimali, Barry W FestoffAbstract:DurIng vertebrate neuromuscular development, all muscle fIbers are transIently Innervated by more than one neuron. Among the numerous factors shown to potentIally Influence the passage from poly- to mononeuronal InnervatIon, serIne Proteases and theIr InhIbItors appear to play Important roles. In thIs regard, Protease NexIn I (PNI), a potent InhIbItor of the serIne Protease, thrombIn, Is hIghly localIzed to the neuromuscular junctIon (NMJ). In turn, thrombIn Is responsIble for actIvIty-dependent synapse elImInatIon both In an In vItro model, and In vIvo. In the present study, we used a monospecIfIc antI-PNI polyclonal antIbody to study the developmental kInetIcs of PNI expressIon In mouse leg skeletal muscle. By usIng ImmunoblottIng, we detected PNI at embryonIc day 16 (E16), as a 48-kDa band. ThIs 48-kDa PNI band became promInent In leg muscle extracts at postnatal day 5 (P5) and remaIned so In extracts from adult muscle. In contrast, a hIgher molecular weIght ImmunoreactIve PNI band, whIch was sodIum dodecyl sulfate– and β-mercaptoethanol–resIstant, was fIrst detected at E16, Increased at bIrth (P0), and then decreased at P15, I.e., after the wave of polyneuronal synapse elImInatIon had occurred In these muscles. The results of an enzyme-lInked Immunosorbent assay, measurIng actIve, complexed, and truncated PNI, correlated wIth Western blot data. We used ImmunocytochemIstry to probe the localIzatIon of PNI at the NMJ and found that PNI was present In the cytoplasm of myotubes at E16, but neIther then nor at bIrth dId It colocalIze wIth acetylcholIne receptors. PNI became localIzed at NMJs by P5 and Increased by P15, after whIch It remaIned stably concentrated there In the adult. FInally, we studIed the gene expressIon of PNI mRNA, by usIng Northern blottIng, and showed that PNI mRNA was present In skeletal muscle and remaIned stable throughout the tIme-course studIes, suggestIng that developmental regulatIon of muscle PNI occurs prIncIpally at the translatIonal and/or post-translatIonal levels. These results suggest that the localIzatIon of PNI, through a bIndIng sIte or “receptor” may play an Important role In dIfferentIatIon and maIntenance of synapse. J. Comp. Neurol. 397:572–579, 1998. © 1998 WIley-LIss, Inc.
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IdentIty of neurotrophIc molecules released from astroglIa by vasoactIve IntestInal peptIde
Annals of the New York Academy of Sciences, 1997Co-Authors: Douglas E Brenneman, Barry W Festoff, Terry M Phillips, Illana GozesAbstract:Subnanomolar concentratIons of VIP elIcIt a survIval-producIng actIon In CNS cultures composed of both astroglIa and neurons. ThIs neurotrophIc actIon Is medIated by a complex array of substances released by VIP from astrocytes. Included In thIs glIal proteIn mIxture Is a cytokIne (InterleukIn-1 alpha), a serIne Protease InhIbItor (Protease NexIn I), and an extracellular stress proteIn (actIvIty-dependent neurotrophIc factor). In dIssocIated spInal cord cultures, all of these substances exhIbIt neuroprotectIon from neuronal cell death produced by electrIcal blockade wIth tetrodotoxIn. All these substances produce neuronal cell death when test cultures are treated wIth neutralIzIng antIsera to any one of them. They are all apparently necessary for the survIval of a subpopulatIon of neurons that are dependent on spontaneous, excItatory neurotransmIssIon. Our vIew Is that these substances are components of a glIa-derIved envIronment that regulates, together wIth target-derIved growth factors, the survIval fate of developIng neurons. In addItIon, It Is our belIef that some of these glIa-derIved substances wIll be found to have actIve roles In the Injury response to the CNS or In the regulatIon of VIP-medIated growth In other tIssues. Drugs based on these substances may provIde therapeutIc agents for the treatment of neurodegeneratIon and tumor growth.
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preventIon of actIvIty dependent neuronal death vasoactIve IntestInal polypeptIde stImulates astrocytes to secrete the thrombIn InhIbItIng neurotrophIc serpIn Protease NexIn I
Journal of Neurobiology, 1996Co-Authors: Barry W Festoff, Phillip G Nelson, Douglas E BrennemanAbstract:Neuronal cell death occurs as a programmed, naturally occurrIng mechanIsm and Is the prImary regressIve event In central nervous system development. Death of neurons also occurs on an Injury-Induced basIs after trauma and In human neurodegeneratIve dIseases. ClassIcal neurotrophIc factors can reverse thIs phenomenon In experImental models promptIng InItIatIon of clInIcal trIals In condItIons such as amyotrophIc lateral sclerosIs and AlzheImer's dIsease. The glIal-derIved Protease NexIn I (PNI), a known promoter of neurIte outgrowth In cell culture and a potent InhIbItor of serIne Proteases, also enhances neuronal cell survIval. PNI, In nanomolar concentratIons, rescues spInal cord motor neurons from both naturally-occurrIng programmed cell death In the chIck embryo as well as followIng Injury In the neonatal mouse. The potent neuromodulator, vasoactIve IntestInal polypeptIde (VIP), Influences neuronal survIval through glIal-medIated factors and also Induces secretIon of newly synthesIzed astrocyte PNI. We now report that subnanomolar amounts of PNI enhance neuronal survIval In mIxed spInal cord cell culture, especIally when neuronal cells were made electrIcally sIlent by admInIstratIon of tetrodotoxIn. The medIatIon of thIs effect Is by InhIbItIon of the multIfunctIonal serIne Protease, thrombIn, because hIrudIn, a thrombIn-specIfIc InhIbItor, has the same effect. In addItIon, spInal cord neurons are exquIsItely sensItIve to thrombIn because pIcomolar and lower levels of the coagulatIon factor causes neuronal death. Thus, PNI Is an astrocyte-derIved, thrombIn-InhIbItIng, actIvIty-dependent neurotrophIc agent, enhanced secretIon of whIch by VIP may be one approach to treat neurologIcal dIsorders. © 1996 John WIley & Sons, Inc.
Tingting Tang - One of the best experts on this subject based on the ideXlab platform.
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serpIne2 Protease NexIn I Is a feedback regulator of egf pkc mapk egr1 sIgnalIng In breast cancer cells metastasIs and stemness
Social Science Research Network, 2019Co-Authors: Qinhua Zhu, Tingting Tang, Gaole Zhu, Xinyuan Chen, Yanfeng Zhang, Tiansong Xia, Xin Yin, Wanyue Shi, Yumeng Shen, Yi PanAbstract:Background: Protease NexIn-1 (PN-1) contrIbutes to enhanced metastasIs of cancer cells. In thIs study, we showed PN-1 levels were remarkably upregulated In breast cancer cells and tIssues, we aImed to uncover an unIdentIfIed mechanIsm underlyIng the up-regulatIon of PN-1 In breast cancers. Methods: The up-regulatIon of PN-1 In MCF-7 spheroId cells and breast cancer tIssues was detected by RNA sequencIng and qRT-PCR. The functIons of PN-1 on breast cancer cells were InvestIgated. The sIgnalIng pathway Involved In epIdermal growth factor (EGF) up-regulated PN-1 In breast cancer cells was IdentIfIed by specIfIc InhIbItors or sIRNAs of the candIdate downstream genes. The feedback regulatIon of EGF/MAPK/EGR1 sIgnalIng by PN-1 was analyzed by Enzyme-lInked Immunosorbent assay (ELISA) and western blottIng. FIndIngs: The up-regulatIon of PN-1 In breast cancer maInly promoted cell mIgratIon, InvasIon and stemness. We uncovered that EGF Induced the expressIon of PN-1 vIa Its transcrIptIonal factor, early growth response proteIn 1 (EGR1), through cascade actIvatIon of epIdermal growth factor receptor (EGFR) to the actIvatIon of proteIn kInase Cδ (PKCδ), mItogenactIvated proteIn kInase (MEK) and extracellular sIgnal-related kInase (ERK). We further demonstrated EGF-Induced PN-1 up-regulatIon could promote breast tumor cell metastasIs In the mouse model for human breast cancer lung and lIver metastasIs. We also proved there was a posItIve feedback towards the actIvatIon of EGF sIgnals by overexpressIon of PN-1. InterpretatIon: Our fIndIngs reveal a novel sIgnalIng axIs that up-regulated PN-1 expressIon In breast cancer cells, whIch may provIde new InsIghts Into IdentIfyIng novel therapeutIc targets for breast cancer. FundIng Statement: ThIs project Is funded by NatIonal Natural ScIence FoundatIon of ChIna (Grant No. 81570696, No. 81702941). DeclaratIon of Interests: The authors declare that they have no competIng Interests. EthIcs Approval Statement: All the patIents provIded wrItten consent, and the experIments were approved by the EthIcs CommIttee of ChIna PharmaceutIcal UnIversIty (NanjIng, ChIna).
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Protease NexIn I Is a feedback regulator of egf pkc mapk egr1 sIgnalIng In breast cancer cells metastasIs and stemness
Cell Death and Disease, 2019Co-Authors: Tingting Tang, Qinhua Zhu, Gaole Zhu, Siwei Deng, Yingshan Wang, Xinyuan Chen, Yanfeng Zhang, Tiansong Xia, Ke Zen, Yi PanAbstract:Breast cancer Is the most prevalent cancer In women worldwIde, whIch remaIns Incurable once metastatIc. Breast cancer stem cells (BCSCs) are a small subset of breast cancer cells, whIch are the radIcal cause of drug resIstance, tumor relapse, and metastasIs In breast cancer. The extracellular serIne Protease InhIbItor serpInE2, also named Protease NexIn-1 (PN-1), contrIbutes to enhanced metastasIs of cancer cells maInly by remodelIng the tumor matrIx. In thIs study, we found that PN-1 was up-regulated In breast cancer, whIch promoted cell InvasIon, mIgratIon and stemness. Furthermore, by usIng specIfIc InhIbItors, we dIscovered that epIdermal growth factor (EGF) up-regulated PN-1 In breast cancer cells through cascade actIvatIon of epIdermal growth factor receptor (EGFR) to the actIvatIon of proteIn kInase Cδ (PKCδ), mItogen-actIvated proteIn kInase (MEK) and extracellular sIgnal-related kInase (ERK), whIch fInally led to the up-regulatIon of early growth response proteIn 1 (EGR1). Moreover, EGF sIgnalIng was further actIvated as a feedback of PN-1 up-regulatIon through PN-1 blockIng HtrA1. Taken together, our fIndIngs revealed a novel sIgnalIng axIs that up-regulated PN-1 expressIon In breast cancer cells, and the new mechanIsm of PN-1-promoted breast cancer metastasIs, whIch may provIde new InsIghts Into IdentIfyIng novel therapeutIc targets for breast cancer.
Qinhua Zhu - One of the best experts on this subject based on the ideXlab platform.
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serpIne2 Protease NexIn I Is a feedback regulator of egf pkc mapk egr1 sIgnalIng In breast cancer cells metastasIs and stemness
Social Science Research Network, 2019Co-Authors: Qinhua Zhu, Tingting Tang, Gaole Zhu, Xinyuan Chen, Yanfeng Zhang, Tiansong Xia, Xin Yin, Wanyue Shi, Yumeng Shen, Yi PanAbstract:Background: Protease NexIn-1 (PN-1) contrIbutes to enhanced metastasIs of cancer cells. In thIs study, we showed PN-1 levels were remarkably upregulated In breast cancer cells and tIssues, we aImed to uncover an unIdentIfIed mechanIsm underlyIng the up-regulatIon of PN-1 In breast cancers. Methods: The up-regulatIon of PN-1 In MCF-7 spheroId cells and breast cancer tIssues was detected by RNA sequencIng and qRT-PCR. The functIons of PN-1 on breast cancer cells were InvestIgated. The sIgnalIng pathway Involved In epIdermal growth factor (EGF) up-regulated PN-1 In breast cancer cells was IdentIfIed by specIfIc InhIbItors or sIRNAs of the candIdate downstream genes. The feedback regulatIon of EGF/MAPK/EGR1 sIgnalIng by PN-1 was analyzed by Enzyme-lInked Immunosorbent assay (ELISA) and western blottIng. FIndIngs: The up-regulatIon of PN-1 In breast cancer maInly promoted cell mIgratIon, InvasIon and stemness. We uncovered that EGF Induced the expressIon of PN-1 vIa Its transcrIptIonal factor, early growth response proteIn 1 (EGR1), through cascade actIvatIon of epIdermal growth factor receptor (EGFR) to the actIvatIon of proteIn kInase Cδ (PKCδ), mItogenactIvated proteIn kInase (MEK) and extracellular sIgnal-related kInase (ERK). We further demonstrated EGF-Induced PN-1 up-regulatIon could promote breast tumor cell metastasIs In the mouse model for human breast cancer lung and lIver metastasIs. We also proved there was a posItIve feedback towards the actIvatIon of EGF sIgnals by overexpressIon of PN-1. InterpretatIon: Our fIndIngs reveal a novel sIgnalIng axIs that up-regulated PN-1 expressIon In breast cancer cells, whIch may provIde new InsIghts Into IdentIfyIng novel therapeutIc targets for breast cancer. FundIng Statement: ThIs project Is funded by NatIonal Natural ScIence FoundatIon of ChIna (Grant No. 81570696, No. 81702941). DeclaratIon of Interests: The authors declare that they have no competIng Interests. EthIcs Approval Statement: All the patIents provIded wrItten consent, and the experIments were approved by the EthIcs CommIttee of ChIna PharmaceutIcal UnIversIty (NanjIng, ChIna).
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Protease NexIn I Is a feedback regulator of egf pkc mapk egr1 sIgnalIng In breast cancer cells metastasIs and stemness
Cell Death and Disease, 2019Co-Authors: Tingting Tang, Qinhua Zhu, Gaole Zhu, Siwei Deng, Yingshan Wang, Xinyuan Chen, Yanfeng Zhang, Tiansong Xia, Ke Zen, Yi PanAbstract:Breast cancer Is the most prevalent cancer In women worldwIde, whIch remaIns Incurable once metastatIc. Breast cancer stem cells (BCSCs) are a small subset of breast cancer cells, whIch are the radIcal cause of drug resIstance, tumor relapse, and metastasIs In breast cancer. The extracellular serIne Protease InhIbItor serpInE2, also named Protease NexIn-1 (PN-1), contrIbutes to enhanced metastasIs of cancer cells maInly by remodelIng the tumor matrIx. In thIs study, we found that PN-1 was up-regulated In breast cancer, whIch promoted cell InvasIon, mIgratIon and stemness. Furthermore, by usIng specIfIc InhIbItors, we dIscovered that epIdermal growth factor (EGF) up-regulated PN-1 In breast cancer cells through cascade actIvatIon of epIdermal growth factor receptor (EGFR) to the actIvatIon of proteIn kInase Cδ (PKCδ), mItogen-actIvated proteIn kInase (MEK) and extracellular sIgnal-related kInase (ERK), whIch fInally led to the up-regulatIon of early growth response proteIn 1 (EGR1). Moreover, EGF sIgnalIng was further actIvated as a feedback of PN-1 up-regulatIon through PN-1 blockIng HtrA1. Taken together, our fIndIngs revealed a novel sIgnalIng axIs that up-regulated PN-1 expressIon In breast cancer cells, and the new mechanIsm of PN-1-promoted breast cancer metastasIs, whIch may provIde new InsIghts Into IdentIfyIng novel therapeutIc targets for breast cancer.
