BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of c...BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of cases.HCC is the most common primary liver cancer.China has the highest incidence and mortality rate of HCC in the world,and it is one of the malignant tumors that seriously threaten the health of Chinese people.The onset of liver cancer is occult,the early cases lack typical clinical symptoms,and most of the patients are already in the middle and late stage when diagnosed.Therefore,it is very important to find new markers for the early detection and diagnosis of liver cancer,improve the therapeutic effect,and improve the prognosis of patients.Protein tyrosine phosphatase non-receptor 2(PTPN2)has been shown to be associated with colorectal cancer,triple-negative breast cancer,non-small cell lung cancer,and prostate cancer,but its biological role and function in tumors remain to be further studied.AIM To combine the results of relevant data obtained from The Cancer Genome Atlas(TCGA)to provide the first in-depth analysis of the biological role of PTPN2 in HCC.METHODS The expression of PTPN2 in HCC was first analyzed based on the TCGA database,and the findings were then verified by immunohistochemical staining,quantitative real-time polymerase chain reaction(qRT-PCR),and immunoblotting.The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features.Finally,the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining.RESULTS The results of immunohistochemical staining,qRT-PCR,and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients.Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways,including cancer-related pathways,the Notch signaling pathway,and the MAPK signaling pathway.Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways,such as the epithelial mesenchymal transition process.A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group.CONCLUSION This study investigated PTPN2 from multiple biological perspectives,revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.展开更多
BACKGROUND Cancerous inhibitor of protein phosphatase 2A(CIP2A)is a newly discovered oncogene.It is an active cell proliferation regulatory factor that inhibits tumor apoptosis in gastric cancer(GC)cells.CIP2A is func...BACKGROUND Cancerous inhibitor of protein phosphatase 2A(CIP2A)is a newly discovered oncogene.It is an active cell proliferation regulatory factor that inhibits tumor apoptosis in gastric cancer(GC)cells.CIP2A is functionally related to chemoresistance in various types of tumors according to recent studies.The underlying mechanism,however,is unknown.Further,the primary treatment regimen for GC is oxaliplatin-based chemotherapy.Nonetheless,it often fails due to chemoresistance of GC cells to oxaliplatin.AIM The goal of this study was to examine CIP2A expression and its association with oxaliplatin resistance in human GC cells.METHODS Immunohistochemistry was used to examine CIP2A expression in GC tissues and adjacent normal tissues.CIP2A expression in GC cell lines was reduced using small interfering RNA.After confirming the silencing efficiency,3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium and flow cytometry assays were used to evaluate cell proliferation and apoptosis caused by oxaliplatin treatment.Further,the key genes and protein changes were verified using realtime quantitative reverse transcription PCR and Western blotting,respectively,before and after intervention.For bioinformatics analysis,we used the R software and Bioconductor project.For statistical analysis,we used GraphPad Prism 6.0 and the Statistical Package for the Social Sciences software version 20.0(IBM,Armonk,United States).RESULTS A high level of CIP2A expression was associated with tumor size,T stage,lymph node metastasis,Tumor Node Metastasis stage,and a poor prognosis.Further,CIP2A expression was higher in GC cells than in normal human gastric epithelial cells.Using small interfering RNA against CIP2A,we discovered that CIP2A knockdown inhibited cell proliferation and significantly increased GC cell sensitivity to oxaliplatin.Moreover,CIP2A knockdown enhanced oxaliplatin-induced apoptosis in GC cells.Hence,high CIP2A levels in GC may be a factor in chemoresistance to oxaliplatin.In human GC cells,CIP2A regulated protein kinase B phosphorylation,and chemical inhibition of the protein kinase B signaling pathway was significantly associated with increased sensitivity to oxaliplatin.Therefore,the protein kinase B signaling pathway was correlated with CIP2Aenhanced chemoresistance of human GC cells to oxaliplatin.CONCLUSION CIP2A expression could be a novel therapeutic strategy for chemoresistance in GC.展开更多
Ischemic stroke can cause blood-brain barrier(BBB)injury,which worsens brain damage induced by stroke.Abnormal expression of tight junction proteins in endothelial cells(ECs)can increase intracellular space and BBB le...Ischemic stroke can cause blood-brain barrier(BBB)injury,which worsens brain damage induced by stroke.Abnormal expression of tight junction proteins in endothelial cells(ECs)can increase intracellular space and BBB leakage.Selective inhibition of mitogen-activated protein kinase,the negative regulatory substrate of mitogen-activated protein kinase phosphatase(MKP)-1,improves tight junction protein function in ECs,and genetic deletion of MKP-1 aggravates ischemic brain injury.However,whether the latter affects BBB integrity,and the cell type-specific mechanism underlying this process,remain unclear.In this study,we established an adult male mouse model of ischemic stroke by occluding the middle cerebral artery for 60 minutes and overexpressed MKP-1 in ECs on the injured side via lentiviral transfection before stroke.We found that overexpression of MKP-1 in ECs reduced infarct volume,reduced the level of inflammatory factors interleukin-1β,interleukin-6,and chemokine C-C motif ligand-2,inhibited vascular injury,and promoted the recovery of sensorimotor and memory/cognitive function.Overexpression of MKP-1 in ECs also inhibited the activation of cerebral ischemia-induced extracellular signal-regulated kinase(ERK)1/2 and the downregulation of occludin expression.Finally,to investigate the mechanism by which MKP-1 exerted these functions in ECs,we established an ischemic stroke model in vitro by depriving the primary endothelial cell of oxygen and glucose,and pharmacologically inhibited the activity of MKP-1 and ERK1/2.Our findings suggest that MKP-1 inhibition aggravates oxygen and glucose deprivation-induced cell death,cell monolayer leakage,and downregulation of occludin expression,and that inhibiting ERK1/2 can reverse these effects.In addition,co-inhibition of MKP-1 and ERK1/2 exhibited similar effects to inhibition of ERK1/2.These findings suggest that overexpression of MKP-1 in ECs can prevent ischemia-induced occludin downregulation and cell death via deactivating ERK1/2,thereby protecting the integrity of BBB,alleviating brain injury,and improving post-stroke prognosis.展开更多
Protein phosphatase 2A(PP2A)is a major serine/threonine phosphatase which participates in the regulation of multiple cellular processes.As a confirmed tumor suppressor,PP2A activity is downregulated in tumors and its ...Protein phosphatase 2A(PP2A)is a major serine/threonine phosphatase which participates in the regulation of multiple cellular processes.As a confirmed tumor suppressor,PP2A activity is downregulated in tumors and its re-activation can induce apoptosis of cancer cells.In the brains of Alzheimer's disease(AD)patients,decreased PP2A activity also plays a key role in promoting tau hyperphosphorylation and A0 generation.In this review,we discussed compounds aiming at modulating PP2A activity in the treatment of cancer or AD.The upstream factors that inactivate PP2A in diseases have not been fully elucidated and further studies are needed.It will help for the refinement and development of novel and clinically tractable PP2A-targeted compounds or therapies for the treatment of tumor and AD.展开更多
背景与目的:蛋白磷酸酶2A抑制剂-2(inhibitor 2 of protein phosphatase 2A,I2PP2A)在包括胃癌的多种肿瘤中过度表达,提示其可能在胃癌的发生中发挥重要作用。为进一步探讨I2PP2A的功能及其在胃癌发生中的作用,建立稳定抑制I2PP2A基因...背景与目的:蛋白磷酸酶2A抑制剂-2(inhibitor 2 of protein phosphatase 2A,I2PP2A)在包括胃癌的多种肿瘤中过度表达,提示其可能在胃癌的发生中发挥重要作用。为进一步探讨I2PP2A的功能及其在胃癌发生中的作用,建立稳定抑制I2PP2A基因表达的人胃癌BGC823细胞株。方法:筛选出I2PP2A基因的RNA干扰(RNA interference,RNAi)有效靶序列,合成靶序列的Oligo DNA并构建p GLV2_sh RNA_I2PP2A慢病毒载体,酶切和测序鉴定正确后,经病毒包装,感染BGC823细胞,经嘌呤霉素筛选稳定表达细胞株,通过实时定量PCR(real-time PCR,RT-PCR)和蛋白[质]印迹法(Western blot)鉴定I2PP2A的表达。结果:重组慢病毒质粒经测序鉴定正确;RT-PCR和Western blot证实干扰I2PP2A后,BGC823细胞株中I2PP2A表达水平明显降低,抑制率约为90%。结论:成功构建了I2PP2A sh RNA慢病毒表达载体,建立了稳定抑制I2PP2A基因表达的人胃癌BGC823细胞株,为进一步研究I2PP2A在胃癌发生中的作用提供了可靠的细胞模型。展开更多
Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2(PTPN2) with the onset of inflammatory bowel disease(IBD) ...Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2(PTPN2) with the onset of inflammatory bowel disease(IBD) and other inflammatory disorders. Expression of PTPN2 is enhanced in actively inflamed intestinal tissue featuring a marked up-regulation in intestinal epithelial cells. PTPN2 deficient mice suffer from severe intestinal and systemic inflammation and display aberrant innate and adaptive immune responses. In particular, PTPN2 is involved in the regulation of inflammatory signalling cascades, and critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses, and finally for maintaining intestinal homeostasis. On one hand, dysfunction of PTPN2 has drastic effects on innate host defence mechanisms, including increased secretion of pro-inflammatory cytokines, limited autophagosome formation in response to invading pathogens, and disruption of the intestinal epithelial barrier. On the other hand, PTPN2 function is crucial for controlling adaptive immune functions, by regulating T cell proliferation and differentiation as well as maintaining T cell tolerance. In this way, dysfunction of PTPN2 contributes to the manifestation of IBD. The aim of this review is to present an overview of recent findings on the role of PTPN2 in intestinal homeostasis and the impact of dysfunctional PTPN2 on intestinal inflammation.展开更多
Protein phosphatase 2 A（PP2 A） was reported to play an important role in cancer development;however,the relationship between PP2 A and cervical cancer development has yet to be fully understood.The present study aim...Protein phosphatase 2 A（PP2 A） was reported to play an important role in cancer development;however,the relationship between PP2 A and cervical cancer development has yet to be fully understood.The present study aimed to explore the role of PP2 A in the development of cervical cancer.Serum levels of PP2 A were detected by ELISA in 23 patients with cervical cancer and 30 patients with benign cervical lesions.Furthermore,the PP2 A activities and the m RNA and protein levels of PP2 A were measured in cervical cancer（n=8） and chronic cervicitis（n=10） tissues.The results showed that the serum levels of PP2 A were significantly reduced in patients with cervical cancer.Further studies showed that not only the activities of PP2 A but also the m RNA and protein levels of PP2 A were significantly decreased in cervical cancer tissues.Wound healing and Transwell assays demonstrated that pharmacological and genetic upregulation of PP2 A could inhibit the migration of He La cells,but the downregulation of PP2 A promoted cellular migration.The activation of PP2 A also inhibited the remodeling of actin and the activity of mitogen-activated protein kinases（MAPKs） including p-JNK,p-p38 and p-ERK.Meanwhile,the activation of PP2 A was found to downregulate MMP-9 levels,which further inhibited the migration and invasion of He La cells.In conclusion,our data suggest that the activity and expression of PP2 A are significantly reduced in cervical cancer tissues,and the activation of PP2 A may inhibit the migration of cervical cancer cells by inhibiting the phosphorylation of p-JNK,p-p38 and the p-ERK/MAPK signaling pathway as well as by downregulating MMP-9,implying that PP2 A plays an important role in cervical cancer development.展开更多
Protein phosphatases play essential roles as negative regulators of kinases and signaling cascades involved in cytoskeletal organization.Protein phosphatase 2A(PP2A)is highly conserved and is the predominant serine/th...Protein phosphatases play essential roles as negative regulators of kinases and signaling cascades involved in cytoskeletal organization.Protein phosphatase 2A(PP2A)is highly conserved and is the predominant serine/threonine phosphatase in the nervous system,constituting more than 70%of all neuronal phosphatases.PP2A is involved in diverse regulatory functions,including cell cycle progression,apoptosis,and DNA repair.Although PP2A has historically been identified as a tumor suppressor,inhibition of PP2A has paradoxically demonstrated potential as a therapeutic target for various cancers.LB100,a water-soluble,small-molecule competitive inhibitor of PP2A,has shown particular promise as a chemo-and radio-sensitizing agent.Preclinical success has led to a profusion of clinical trials on LB100 adjuvant therapies,including a phase I trial in extensive-stage small-cell lung cancer,a phase I/II trial in myelodysplastic syndrome,a phase II trial in recurrent glioblastoma,and a completed phase I trial assessing the safety of LB100 and docetaxel in various relapsed solid tumors.Herein,we review the development of LB100,the role of PP2A in cancer biology,and recent advances in targeting PP2A inhibition in immunotherapy.展开更多
Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B （PTP-1B） inhibitors for type 2 diabetes mellitus （T2DM）. In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic...Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B （PTP-1B） inhibitors for type 2 diabetes mellitus （T2DM）. In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic acid derivatives were divided into a training set （34 compounds） and a test set （18 compounds）. The highly reliable and predictive 3D-QSAR models were constructed by CoMFA, CoMSIA and topomer CoMFA methods, respectively. The results showed that the cross validated coefficient （q2） and non-cross-validated coefficient （R2） were 0.554 and 0.999 in the CoMFA model, 0.675 and 0.971 in the CoMSIA model, and 0.628 and 0.939 in the topomer CoMFA model, which suggests that three models are robust and have good exterior predictive capabilities. Furthermore, ten novel inhibitors with much higher inhibitory potency were designed. Our design strategy was that （i） the electronegative substituents （Cl, -CH2OH, OH and -CH2Cl） were introduced into the double bond of ring C, （ii） the hydrogen bond acceptor groups （C≡N and N atom）, electronegative groups （C≡N, N atom, -COOH and -COOCH3） and bulky substituents （C6H5N） were connected to the C-3 position, which would result in generating potent and selective PTP-1B inhibitors. We expect that the results in this paper have the potential to facilitate the process of design and to develop new potent PTP-1B inhibitors.展开更多
BACKGROUND Protein phosphatase 2 regulatory subunit B''alpha(PPP2R3A)gene has been reported in other tumors,but the influence of PPP2R3A gene expression on the occurrence,development,and prognosis of hepatocel...BACKGROUND Protein phosphatase 2 regulatory subunit B''alpha(PPP2R3A)gene has been reported in other tumors,but the influence of PPP2R3A gene expression on the occurrence,development,and prognosis of hepatocellular carcinoma(HCC)remains unclear.AIM To investigate whether the PPP2R3A gene could be used to predict tumor recurrence and survival of HCC patients after liver transplantation(LT).METHODS Diseased liver tissues of HCC patients after LT were collected as well as their clinical data and follow-up information.The immunohistochemical method was used to detect the expression of PPP2R3A protein in the tissues of 108 patients with primary liver cancer.Theχ2 test was used to analyze the relationship between PPP2R3A protein expression levels and the clinicopathological features of tumors.The Kaplan-Meier method was used to analyze overall postoperative survival.The COX proportional hazard model was used to analyze adverse prognostic factors.RESULTS Immunohistochemistry showed that the PPP2R3A protein was mainly expressed in the cytoplasm of HCC cells.Compared to corresponding peritumoral tissues,expression was higher in HCC tissues(P≤0.001).Correlation analysis showed that high PPP2R3A expression was correlated with preoperative serum alphafetoprotein(AFP)levels(P=0.003),tumor-node-metastasis-t stage(P≤0.001),and envelope invasion(P=0.001).Univariate analysis showed that overall survival(P≤0.001)and recurrence-free survival(P=0.025)of patients with high PPP2R3A expression(≥4 points)were poor compared to those with low expression(<4 points).The overall survival rates or recurrence-free survival rates at 1,2,and 3 years with high PPP2R3A expression were 73%,38%,and 23%or 31%,23%,and 23%,respectively.Multivariate analysis showed that high PPP2R3A expression(hazard ratio=2.900,95%confidence interval:1.411–5.960,P=0.004)was an independent survival risk factor of HCC patients after LT,and it was also an independent predictor of postoperative tumor recurrence.This study also showed in patients with AFP≥400 ng/mL,the overall survival(P≤0.001)and recurrencefree survival(P=0.023)of those with high PPP2R3A expression were significantly worse compared to those with low PPP2R3A expression.When PPP2R3A expression was low,the overall survival rate(P=0.461)or recurrence-free survival rate(P=0.072)after LT in patients with AFP<400 ng/mL and≥400 ng/mL was not significantly difference.The 1,2,and 3 year survival rate of patients with low PPP2R3A expression and AFP<400 ng/mL were 98%,80%,and 69%,respectively,while patients who met Hangzhou criteria had a posttransplant 1,2,and 3 years overall survival rate of 89%,66%,and 55%,respectively.CONCLUSION High expression of PPP2R3A might be a potential marker for predicting poor prognosis of HCC after LT.Combined with serum AFP levels,PPP2R3A might enhance the accuracy of predicting HCC outcome in patients after LT and supplement the efficacy of the Hangzhou criteria.展开更多
Acute pancreatitis is an inflammation of the pancreas that may lead to systemic inflammatory response syndrome and death due to multiple organ failure. Acinar cells, together with leukocytes, trigger the inflammatory ...Acute pancreatitis is an inflammation of the pancreas that may lead to systemic inflammatory response syndrome and death due to multiple organ failure. Acinar cells, together with leukocytes, trigger the inflammatory cascade in response to local damage of the pancreas. Amplification of the inflammatory cascade requires up-regulation of proinflammatory cytokines and this process is mediated not only by nuclear factor κB but also by chromatinmodifying complexes and chromatin remodeling. Among the different families of histone acetyltransferases, the p300/CBP family seems to be particularly associated with the inflammatory process. cAMP activates gene expression via the cAMP-responsive element (CRE) and the transcription factor CRE-binding protein (CREB). CREB can be phosphorylated and activated by different kinases, such as protein kinase A and MAPK, and then it recruits the histone acetyltransferase co-activator CREB-binding protein (CBP) and its homologue p300. The recruitment of CBP/p300 and changes in the level of histone acetylation are required for transcription activation. Transcriptional repression is also a dynamic and essential mechanism of down-regulation of genes for resolution of inflammation, which seems to be mediated mainly by protein phosphatases (PP1, PP2A and MKP1) and histone deacetylases(HDACs) .Class HDACs are key transcriptional regulators whose activities are controlled via phosphorylationdependent nucleo/cytoplasmic shuttling. PP2A is responsible for dephosphorylation of class HDACs, triggeringnuclear localization and repression of target genes, whereas phosphorylation triggers cytoplasmic localization leading to activation of target genes. The potential benefit from treatment with phosphodiesterase inhibitors and histone deacetylase inhibitors is discussed.展开更多
The Ikaros gene encodes a zinc finger,DNA-binding protein that regulates gene transcription and chromatin remodeling.Ikaros is a master regulator of hematopoiesis and an established tumor suppressor.Moderate alteratio...The Ikaros gene encodes a zinc finger,DNA-binding protein that regulates gene transcription and chromatin remodeling.Ikaros is a master regulator of hematopoiesis and an established tumor suppressor.Moderate alteration of Ikaros activity (e.g.haploinsufficiency) appears to be sufficient to promote malignant transformation in human hematopoietic cells.This raises questions about the mechanisms that normally regulate Ikaros function and the potential of these mechanisms to contribute to the development of leukemia.The focus of this review is the regulation of Ikaros function by phosphorylation/dephosphorylation.Site-specific phosphorylation of Ikaros by casein kinase 2 (CK2) controls Ikaros DNA-binding ability and subcellular localization.As a consequence,the ability of Ikaros to regulate cell cycle progression,chromatin remodeling,target gene expression,and thymocyte differentiation are controlled by CK2.In addition,hyperphosphorylation of Ikaros by CK2 leads to decreased Ikaros levels due to ubiquitinmediated degradation.Dephosphorylation of Ikaros by protein phosphatase 1 (PP1) acts in opposition to CK2 to increase Ikaros stability and restore Ikaros DNA binding ability and pericentromeric localization.Thus,the CK2 and PP1 pathways act in concert to regulate Ikaros activity in hematopoiesis and as a tumor suppressor.This highlights the importance of these signal transduction pathways as potential mediators of leukemogenesis via their role in regulating the activities of Ikaros.展开更多
Hyperphosphorylation of Tau in Alzheimer＇s disease （AD） brain appears to be caused by a down-regulation of protein phospbatase 2A （PP2A）. In this study, we selectively inhibited PP2A by injection of okadaic acid...Hyperphosphorylation of Tau in Alzheimer＇s disease （AD） brain appears to be caused by a down-regulation of protein phospbatase 2A （PP2A）. In this study, we selectively inhibited PP2A by injection of okadaic acid （OA） into the Meynert nucleus basalis of rats and found that 0.4 pmol of OA injeetion induced approximately 60% inhibition of PP2A 24 h after injection, 13% inhibition 48 h after injection and no obvious inhibition 72 h after injection. Hyperphosphorylation of Tau at Ser-198/ Ser-199/Ser-202 and Ser-396/Ser-404 and spatial memory deficit of rats were induced 24 h after 0. d prnol of OA injection. This study suggests that a dowreregulation of PP2A may underlie almormal hyperphosphorylation of cytoskeletal proteins leading to neurofibrillary degeneration in AD.展开更多
文摘BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of cases.HCC is the most common primary liver cancer.China has the highest incidence and mortality rate of HCC in the world,and it is one of the malignant tumors that seriously threaten the health of Chinese people.The onset of liver cancer is occult,the early cases lack typical clinical symptoms,and most of the patients are already in the middle and late stage when diagnosed.Therefore,it is very important to find new markers for the early detection and diagnosis of liver cancer,improve the therapeutic effect,and improve the prognosis of patients.Protein tyrosine phosphatase non-receptor 2(PTPN2)has been shown to be associated with colorectal cancer,triple-negative breast cancer,non-small cell lung cancer,and prostate cancer,but its biological role and function in tumors remain to be further studied.AIM To combine the results of relevant data obtained from The Cancer Genome Atlas(TCGA)to provide the first in-depth analysis of the biological role of PTPN2 in HCC.METHODS The expression of PTPN2 in HCC was first analyzed based on the TCGA database,and the findings were then verified by immunohistochemical staining,quantitative real-time polymerase chain reaction(qRT-PCR),and immunoblotting.The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features.Finally,the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining.RESULTS The results of immunohistochemical staining,qRT-PCR,and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients.Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways,including cancer-related pathways,the Notch signaling pathway,and the MAPK signaling pathway.Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways,such as the epithelial mesenchymal transition process.A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group.CONCLUSION This study investigated PTPN2 from multiple biological perspectives,revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.
基金Supported by This work was supported by the Natural Science Foundation of Gansu Province,China,No.17JR5RA272 and No.22JR5RA923the Research Fund Project of The First Hospital of Lanzhou University,No.ldyyyn2021-120,No.ldyyyn2020-98 and No.ldyyyn2021-30.
文摘BACKGROUND Cancerous inhibitor of protein phosphatase 2A(CIP2A)is a newly discovered oncogene.It is an active cell proliferation regulatory factor that inhibits tumor apoptosis in gastric cancer(GC)cells.CIP2A is functionally related to chemoresistance in various types of tumors according to recent studies.The underlying mechanism,however,is unknown.Further,the primary treatment regimen for GC is oxaliplatin-based chemotherapy.Nonetheless,it often fails due to chemoresistance of GC cells to oxaliplatin.AIM The goal of this study was to examine CIP2A expression and its association with oxaliplatin resistance in human GC cells.METHODS Immunohistochemistry was used to examine CIP2A expression in GC tissues and adjacent normal tissues.CIP2A expression in GC cell lines was reduced using small interfering RNA.After confirming the silencing efficiency,3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium and flow cytometry assays were used to evaluate cell proliferation and apoptosis caused by oxaliplatin treatment.Further,the key genes and protein changes were verified using realtime quantitative reverse transcription PCR and Western blotting,respectively,before and after intervention.For bioinformatics analysis,we used the R software and Bioconductor project.For statistical analysis,we used GraphPad Prism 6.0 and the Statistical Package for the Social Sciences software version 20.0(IBM,Armonk,United States).RESULTS A high level of CIP2A expression was associated with tumor size,T stage,lymph node metastasis,Tumor Node Metastasis stage,and a poor prognosis.Further,CIP2A expression was higher in GC cells than in normal human gastric epithelial cells.Using small interfering RNA against CIP2A,we discovered that CIP2A knockdown inhibited cell proliferation and significantly increased GC cell sensitivity to oxaliplatin.Moreover,CIP2A knockdown enhanced oxaliplatin-induced apoptosis in GC cells.Hence,high CIP2A levels in GC may be a factor in chemoresistance to oxaliplatin.In human GC cells,CIP2A regulated protein kinase B phosphorylation,and chemical inhibition of the protein kinase B signaling pathway was significantly associated with increased sensitivity to oxaliplatin.Therefore,the protein kinase B signaling pathway was correlated with CIP2Aenhanced chemoresistance of human GC cells to oxaliplatin.CONCLUSION CIP2A expression could be a novel therapeutic strategy for chemoresistance in GC.
基金supported by Research Start-up Funding of Shenzhen Traditional Chinese Medicine Hospital,No.2021-07(to FB)Sanming Project of Medicine in Shenzhen,No.SZZYSM 202111011(to XDQ and FB)+1 种基金Key Discipline Established by Zhejiang Province,Jiaxing City Jointly-Pain Medicine,No.2019-ss-ttyx(to LSX)Jiaxing Key Laboratory of Neurology and Pain Medicine,No.[2014]81(to LSX)。
文摘Ischemic stroke can cause blood-brain barrier(BBB)injury,which worsens brain damage induced by stroke.Abnormal expression of tight junction proteins in endothelial cells(ECs)can increase intracellular space and BBB leakage.Selective inhibition of mitogen-activated protein kinase,the negative regulatory substrate of mitogen-activated protein kinase phosphatase(MKP)-1,improves tight junction protein function in ECs,and genetic deletion of MKP-1 aggravates ischemic brain injury.However,whether the latter affects BBB integrity,and the cell type-specific mechanism underlying this process,remain unclear.In this study,we established an adult male mouse model of ischemic stroke by occluding the middle cerebral artery for 60 minutes and overexpressed MKP-1 in ECs on the injured side via lentiviral transfection before stroke.We found that overexpression of MKP-1 in ECs reduced infarct volume,reduced the level of inflammatory factors interleukin-1β,interleukin-6,and chemokine C-C motif ligand-2,inhibited vascular injury,and promoted the recovery of sensorimotor and memory/cognitive function.Overexpression of MKP-1 in ECs also inhibited the activation of cerebral ischemia-induced extracellular signal-regulated kinase(ERK)1/2 and the downregulation of occludin expression.Finally,to investigate the mechanism by which MKP-1 exerted these functions in ECs,we established an ischemic stroke model in vitro by depriving the primary endothelial cell of oxygen and glucose,and pharmacologically inhibited the activity of MKP-1 and ERK1/2.Our findings suggest that MKP-1 inhibition aggravates oxygen and glucose deprivation-induced cell death,cell monolayer leakage,and downregulation of occludin expression,and that inhibiting ERK1/2 can reverse these effects.In addition,co-inhibition of MKP-1 and ERK1/2 exhibited similar effects to inhibition of ERK1/2.These findings suggest that overexpression of MKP-1 in ECs can prevent ischemia-induced occludin downregulation and cell death via deactivating ERK1/2,thereby protecting the integrity of BBB,alleviating brain injury,and improving post-stroke prognosis.
基金grants from National Natural Science Foundation of China(No.31970964 and No.31771189)Natural Science Foundation of Hubei Province,China(No.2017CFA065)Wuhan Health and Family Planning Commission(No.WX18C17).
文摘Protein phosphatase 2A(PP2A)is a major serine/threonine phosphatase which participates in the regulation of multiple cellular processes.As a confirmed tumor suppressor,PP2A activity is downregulated in tumors and its re-activation can induce apoptosis of cancer cells.In the brains of Alzheimer's disease(AD)patients,decreased PP2A activity also plays a key role in promoting tau hyperphosphorylation and A0 generation.In this review,we discussed compounds aiming at modulating PP2A activity in the treatment of cancer or AD.The upstream factors that inactivate PP2A in diseases have not been fully elucidated and further studies are needed.It will help for the refinement and development of novel and clinically tractable PP2A-targeted compounds or therapies for the treatment of tumor and AD.
文摘背景与目的:蛋白磷酸酶2A抑制剂-2(inhibitor 2 of protein phosphatase 2A,I2PP2A)在包括胃癌的多种肿瘤中过度表达,提示其可能在胃癌的发生中发挥重要作用。为进一步探讨I2PP2A的功能及其在胃癌发生中的作用,建立稳定抑制I2PP2A基因表达的人胃癌BGC823细胞株。方法:筛选出I2PP2A基因的RNA干扰(RNA interference,RNAi)有效靶序列,合成靶序列的Oligo DNA并构建p GLV2_sh RNA_I2PP2A慢病毒载体,酶切和测序鉴定正确后,经病毒包装,感染BGC823细胞,经嘌呤霉素筛选稳定表达细胞株,通过实时定量PCR(real-time PCR,RT-PCR)和蛋白[质]印迹法(Western blot)鉴定I2PP2A的表达。结果:重组慢病毒质粒经测序鉴定正确;RT-PCR和Western blot证实干扰I2PP2A后,BGC823细胞株中I2PP2A表达水平明显降低,抑制率约为90%。结论:成功构建了I2PP2A sh RNA慢病毒表达载体,建立了稳定抑制I2PP2A基因表达的人胃癌BGC823细胞株,为进一步研究I2PP2A在胃癌发生中的作用提供了可靠的细胞模型。
基金Supported by Grants from the Swiss National Science Foundation(SNF)to MSGrant No.314730-146204 and No.CRSII3_154488/1(to Rogler G)+2 种基金Grant No.310030-120312the Swiss IBD CohortGrant No.3347CO-108792
文摘Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2(PTPN2) with the onset of inflammatory bowel disease(IBD) and other inflammatory disorders. Expression of PTPN2 is enhanced in actively inflamed intestinal tissue featuring a marked up-regulation in intestinal epithelial cells. PTPN2 deficient mice suffer from severe intestinal and systemic inflammation and display aberrant innate and adaptive immune responses. In particular, PTPN2 is involved in the regulation of inflammatory signalling cascades, and critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses, and finally for maintaining intestinal homeostasis. On one hand, dysfunction of PTPN2 has drastic effects on innate host defence mechanisms, including increased secretion of pro-inflammatory cytokines, limited autophagosome formation in response to invading pathogens, and disruption of the intestinal epithelial barrier. On the other hand, PTPN2 function is crucial for controlling adaptive immune functions, by regulating T cell proliferation and differentiation as well as maintaining T cell tolerance. In this way, dysfunction of PTPN2 contributes to the manifestation of IBD. The aim of this review is to present an overview of recent findings on the role of PTPN2 in intestinal homeostasis and the impact of dysfunctional PTPN2 on intestinal inflammation.
基金supported by the National Natural Science Foundation of China(No.81100959)Natural Science Foundation of Hubei Province(Nos.2015CFB185,2015CFB723)National Clinical Key Specialty Construction Projects of Ministry of Health of China(No.2010-305)
文摘Protein phosphatase 2 A（PP2 A） was reported to play an important role in cancer development;however,the relationship between PP2 A and cervical cancer development has yet to be fully understood.The present study aimed to explore the role of PP2 A in the development of cervical cancer.Serum levels of PP2 A were detected by ELISA in 23 patients with cervical cancer and 30 patients with benign cervical lesions.Furthermore,the PP2 A activities and the m RNA and protein levels of PP2 A were measured in cervical cancer（n=8） and chronic cervicitis（n=10） tissues.The results showed that the serum levels of PP2 A were significantly reduced in patients with cervical cancer.Further studies showed that not only the activities of PP2 A but also the m RNA and protein levels of PP2 A were significantly decreased in cervical cancer tissues.Wound healing and Transwell assays demonstrated that pharmacological and genetic upregulation of PP2 A could inhibit the migration of He La cells,but the downregulation of PP2 A promoted cellular migration.The activation of PP2 A also inhibited the remodeling of actin and the activity of mitogen-activated protein kinases（MAPKs） including p-JNK,p-p38 and p-ERK.Meanwhile,the activation of PP2 A was found to downregulate MMP-9 levels,which further inhibited the migration and invasion of He La cells.In conclusion,our data suggest that the activity and expression of PP2 A are significantly reduced in cervical cancer tissues,and the activation of PP2 A may inhibit the migration of cervical cancer cells by inhibiting the phosphorylation of p-JNK,p-p38 and the p-ERK/MAPK signaling pathway as well as by downregulating MMP-9,implying that PP2 A plays an important role in cervical cancer development.
基金the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundationthe American Association for Dental Research+2 种基金the Colgate-Palmolive Companyprivate donorssupported partly by the Intramural Research Program at the National Cancer Institute at the NIH
文摘Protein phosphatases play essential roles as negative regulators of kinases and signaling cascades involved in cytoskeletal organization.Protein phosphatase 2A(PP2A)is highly conserved and is the predominant serine/threonine phosphatase in the nervous system,constituting more than 70%of all neuronal phosphatases.PP2A is involved in diverse regulatory functions,including cell cycle progression,apoptosis,and DNA repair.Although PP2A has historically been identified as a tumor suppressor,inhibition of PP2A has paradoxically demonstrated potential as a therapeutic target for various cancers.LB100,a water-soluble,small-molecule competitive inhibitor of PP2A,has shown particular promise as a chemo-and radio-sensitizing agent.Preclinical success has led to a profusion of clinical trials on LB100 adjuvant therapies,including a phase I trial in extensive-stage small-cell lung cancer,a phase I/II trial in myelodysplastic syndrome,a phase II trial in recurrent glioblastoma,and a completed phase I trial assessing the safety of LB100 and docetaxel in various relapsed solid tumors.Herein,we review the development of LB100,the role of PP2A in cancer biology,and recent advances in targeting PP2A inhibition in immunotherapy.
基金Supported by the Natural Science Foundation of Guangxi Province(Nos.2013GXNSFAA019019 and 2013GXNSFAA019041)
文摘Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B （PTP-1B） inhibitors for type 2 diabetes mellitus （T2DM）. In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic acid derivatives were divided into a training set （34 compounds） and a test set （18 compounds）. The highly reliable and predictive 3D-QSAR models were constructed by CoMFA, CoMSIA and topomer CoMFA methods, respectively. The results showed that the cross validated coefficient （q2） and non-cross-validated coefficient （R2） were 0.554 and 0.999 in the CoMFA model, 0.675 and 0.971 in the CoMSIA model, and 0.628 and 0.939 in the topomer CoMFA model, which suggests that three models are robust and have good exterior predictive capabilities. Furthermore, ten novel inhibitors with much higher inhibitory potency were designed. Our design strategy was that （i） the electronegative substituents （Cl, -CH2OH, OH and -CH2Cl） were introduced into the double bond of ring C, （ii） the hydrogen bond acceptor groups （C≡N and N atom）, electronegative groups （C≡N, N atom, -COOH and -COOCH3） and bulky substituents （C6H5N） were connected to the C-3 position, which would result in generating potent and selective PTP-1B inhibitors. We expect that the results in this paper have the potential to facilitate the process of design and to develop new potent PTP-1B inhibitors.
基金National Natural Science Foundation of China,No.81372595.
文摘BACKGROUND Protein phosphatase 2 regulatory subunit B''alpha(PPP2R3A)gene has been reported in other tumors,but the influence of PPP2R3A gene expression on the occurrence,development,and prognosis of hepatocellular carcinoma(HCC)remains unclear.AIM To investigate whether the PPP2R3A gene could be used to predict tumor recurrence and survival of HCC patients after liver transplantation(LT).METHODS Diseased liver tissues of HCC patients after LT were collected as well as their clinical data and follow-up information.The immunohistochemical method was used to detect the expression of PPP2R3A protein in the tissues of 108 patients with primary liver cancer.Theχ2 test was used to analyze the relationship between PPP2R3A protein expression levels and the clinicopathological features of tumors.The Kaplan-Meier method was used to analyze overall postoperative survival.The COX proportional hazard model was used to analyze adverse prognostic factors.RESULTS Immunohistochemistry showed that the PPP2R3A protein was mainly expressed in the cytoplasm of HCC cells.Compared to corresponding peritumoral tissues,expression was higher in HCC tissues(P≤0.001).Correlation analysis showed that high PPP2R3A expression was correlated with preoperative serum alphafetoprotein(AFP)levels(P=0.003),tumor-node-metastasis-t stage(P≤0.001),and envelope invasion(P=0.001).Univariate analysis showed that overall survival(P≤0.001)and recurrence-free survival(P=0.025)of patients with high PPP2R3A expression(≥4 points)were poor compared to those with low expression(<4 points).The overall survival rates or recurrence-free survival rates at 1,2,and 3 years with high PPP2R3A expression were 73%,38%,and 23%or 31%,23%,and 23%,respectively.Multivariate analysis showed that high PPP2R3A expression(hazard ratio=2.900,95%confidence interval:1.411–5.960,P=0.004)was an independent survival risk factor of HCC patients after LT,and it was also an independent predictor of postoperative tumor recurrence.This study also showed in patients with AFP≥400 ng/mL,the overall survival(P≤0.001)and recurrencefree survival(P=0.023)of those with high PPP2R3A expression were significantly worse compared to those with low PPP2R3A expression.When PPP2R3A expression was low,the overall survival rate(P=0.461)or recurrence-free survival rate(P=0.072)after LT in patients with AFP<400 ng/mL and≥400 ng/mL was not significantly difference.The 1,2,and 3 year survival rate of patients with low PPP2R3A expression and AFP<400 ng/mL were 98%,80%,and 69%,respectively,while patients who met Hangzhou criteria had a posttransplant 1,2,and 3 years overall survival rate of 89%,66%,and 55%,respectively.CONCLUSION High expression of PPP2R3A might be a potential marker for predicting poor prognosis of HCC after LT.Combined with serum AFP levels,PPP2R3A might enhance the accuracy of predicting HCC outcome in patients after LT and supplement the efficacy of the Hangzhou criteria.
基金Supported by Grants SAF2006-06963, SAF2009-09500 and Consolider CSD-2007-00020 to Sastre J BFU2007-63120 and CSD2006-49 to López-Rodas G
文摘Acute pancreatitis is an inflammation of the pancreas that may lead to systemic inflammatory response syndrome and death due to multiple organ failure. Acinar cells, together with leukocytes, trigger the inflammatory cascade in response to local damage of the pancreas. Amplification of the inflammatory cascade requires up-regulation of proinflammatory cytokines and this process is mediated not only by nuclear factor κB but also by chromatinmodifying complexes and chromatin remodeling. Among the different families of histone acetyltransferases, the p300/CBP family seems to be particularly associated with the inflammatory process. cAMP activates gene expression via the cAMP-responsive element (CRE) and the transcription factor CRE-binding protein (CREB). CREB can be phosphorylated and activated by different kinases, such as protein kinase A and MAPK, and then it recruits the histone acetyltransferase co-activator CREB-binding protein (CBP) and its homologue p300. The recruitment of CBP/p300 and changes in the level of histone acetylation are required for transcription activation. Transcriptional repression is also a dynamic and essential mechanism of down-regulation of genes for resolution of inflammation, which seems to be mediated mainly by protein phosphatases (PP1, PP2A and MKP1) and histone deacetylases(HDACs) .Class HDACs are key transcriptional regulators whose activities are controlled via phosphorylationdependent nucleo/cytoplasmic shuttling. PP2A is responsible for dephosphorylation of class HDACs, triggeringnuclear localization and repression of target genes, whereas phosphorylation triggers cytoplasmic localization leading to activation of target genes. The potential benefit from treatment with phosphodiesterase inhibitors and histone deacetylase inhibitors is discussed.
基金Supported by (in part) An NIH R01 HL095120 grant,a St.Baldrick’s Foundation Career Development Award,the Four Diamonds Fund of the Pennsylvania State University College of Medicine,and the John Wawrynovic Leukemia Research Scholar Endowment (SD)
文摘The Ikaros gene encodes a zinc finger,DNA-binding protein that regulates gene transcription and chromatin remodeling.Ikaros is a master regulator of hematopoiesis and an established tumor suppressor.Moderate alteration of Ikaros activity (e.g.haploinsufficiency) appears to be sufficient to promote malignant transformation in human hematopoietic cells.This raises questions about the mechanisms that normally regulate Ikaros function and the potential of these mechanisms to contribute to the development of leukemia.The focus of this review is the regulation of Ikaros function by phosphorylation/dephosphorylation.Site-specific phosphorylation of Ikaros by casein kinase 2 (CK2) controls Ikaros DNA-binding ability and subcellular localization.As a consequence,the ability of Ikaros to regulate cell cycle progression,chromatin remodeling,target gene expression,and thymocyte differentiation are controlled by CK2.In addition,hyperphosphorylation of Ikaros by CK2 leads to decreased Ikaros levels due to ubiquitinmediated degradation.Dephosphorylation of Ikaros by protein phosphatase 1 (PP1) acts in opposition to CK2 to increase Ikaros stability and restore Ikaros DNA binding ability and pericentromeric localization.Thus,the CK2 and PP1 pathways act in concert to regulate Ikaros activity in hematopoiesis and as a tumor suppressor.This highlights the importance of these signal transduction pathways as potential mediators of leukemogenesis via their role in regulating the activities of Ikaros.
基金Supported by the National Natural Science Foundation of China(30370560 ,39925012 ,30100057 ,30170221) and a Grant fromthe Li Founda-tion, USA
文摘Hyperphosphorylation of Tau in Alzheimer＇s disease （AD） brain appears to be caused by a down-regulation of protein phospbatase 2A （PP2A）. In this study, we selectively inhibited PP2A by injection of okadaic acid （OA） into the Meynert nucleus basalis of rats and found that 0.4 pmol of OA injeetion induced approximately 60% inhibition of PP2A 24 h after injection, 13% inhibition 48 h after injection and no obvious inhibition 72 h after injection. Hyperphosphorylation of Tau at Ser-198/ Ser-199/Ser-202 and Ser-396/Ser-404 and spatial memory deficit of rats were induced 24 h after 0. d prnol of OA injection. This study suggests that a dowreregulation of PP2A may underlie almormal hyperphosphorylation of cytoskeletal proteins leading to neurofibrillary degeneration in AD.
