AIM:To investigate the role of FAT10 and mutant p53 in the pathogenesis,severity and prognosis of gastric cancer.METHODS:FAT10,mutant p53 mRNA and protein levels were measured by reverse transcription(RT)-PCR and immu...AIM:To investigate the role of FAT10 and mutant p53 in the pathogenesis,severity and prognosis of gastric cancer.METHODS:FAT10,mutant p53 mRNA and protein levels were measured by reverse transcription(RT)-PCR and immunohistochemistry in gastric cancer tissue(n = 62),tumoradjacent tissue(n = 62) and normal gastric tissue(n = 62).Relation of FAT10 and mutant p53 expression with clinicopathological features and clinical outcomes of gastric cancer patients were analyzed.RESULTS:The FAT10,mutant p53 mRNA and protein levels were signif icantly higher in gastric cancer than in its adjacent and normal tissue.The FAT10 and mutant p53 levels in gastric cancer tissue were significantly correlated with lymph node metastasis and tumor,nodes,metastasis(TNM) staging.Moreover,the high FAT10 level was associated with the overall survival rate of patients.Multivariate Cox-proportional hazards model analysis showed that mRNA and protein levels of FAT10 and mutant p53,lymph node metastasis,distant metastasis and TNM stage were the independent prognostic factors for gastric cancer.CONCLUSION:FAT10 may be involved in gastric carcinogenesis,and is a potential marker for the prognosis of gastric cancer patients.FAT10 and mutant p53 may play a common role in the carcinogenesis of gastric cancer.展开更多
Objective To investigate the role of mutated mismatch repair gene hMSH2 and mutant p53 gene in the carcinogenesis and development of sporadic digestive tract tumors. Methods hMSH2 gene in normal and tumor tissue of...Objective To investigate the role of mutated mismatch repair gene hMSH2 and mutant p53 gene in the carcinogenesis and development of sporadic digestive tract tumors. Methods hMSH2 gene in normal and tumor tissue of 30 digestive tract tumor specimens was examined using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) silver staining. The PCR product with an abnormal strand was sequenced directly. Mutant p53 protein in the tumor tissue was analyzed immunohistochemically. Results Six patients were identified as having mutated strands, three on hMSH2 exon 1 and three on hMSH2 exon 5. DNA sequencing revealed that all 6 patients had mutated basic groups that led to decrease in function of the hMSH2 protein. Forty percent (12/30) of patients were p53 positive. The frequency of mutated hMSH2 in p53 positive patients (41.7%) was significantly higher than in p53 negative patients (5.6%, P<0.05). Conclusion The mutation of hMSH2 plays an important role in the carcinogenesis and development of digestive tract tumors through stimulating p53 mutation.展开更多
The tumor suppressor p53 protein is either lost or mutated in about half of all human cancers.Loss of p53 function is well known to influence cell spreading,migration and invasion.While expression of mutant p53 is not...The tumor suppressor p53 protein is either lost or mutated in about half of all human cancers.Loss of p53 function is well known to influence cell spreading,migration and invasion.While expression of mutant p53 is not equivalent to p53 loss,mutant p53 can acquire new functions to drive cell spreading and migration via different mechanisms.In our study,we found that mutant p53 significantly increased cell spreading and migration when comparing with p53-null cells.RNA-Seq analysis suggested that Rho GTPase activating protein 44(ARHGAP44) is a new target of mutant p53,which suppressed AKHGAP44 transcription.ARHGAP44 has GAP activity and catalyze GTP hydrolysis on Cdc42.Higher level of GTP-Cdc42 was correlated with increase expression of mutant p53 and reduced ARHGAP44.Importantly,wt-ARHGAP44 but not mutant ARHGAP44(R291A) suppressed mutant p53 mediated cell spreading and migration.Bioinformatics analysis indicated lower expression of ARHGAP44 in lung carcinoma compared with normal tissues,which was verified by RT-qPCR using specimens from patients.More interestingly,ARHGAP44 mRNA level was lower in tumors with mutant p53 than those with normal p53.Collectively,our results disclose a new mechanism by which mutant p53 stimulates cell spreading and migration.展开更多
B-cell CLL/lymphoma 7 protein family member C (BCL7C) located at chromosome 16p11.2 shares partial sequence homology with the other two family members, BCL7A and BCL7B. Its role in cancer remains completely unknown. H...B-cell CLL/lymphoma 7 protein family member C (BCL7C) located at chromosome 16p11.2 shares partial sequence homology with the other two family members, BCL7A and BCL7B. Its role in cancer remains completely unknown. Here, we report our finding of its tumor-suppressive role in ovarian cancer. Supporting this is that BCL7C is downregulated in human ovarian carcinomas, and its underexpression is associated with unfavorable prognosis of ovarian cancer as well as some other types of human cancers. Also, ectopic BCL7C restrains cell proliferation and invasion of ovarian cancer cells. Consistently, depletion of BCL7C reduces apoptosis and promotes cell proliferation and invasion of these cancer cells. Mechanistically, BCL7C suppresses mutant p53-mediated gene transcription by binding to mutant p53, while knockdown of BCL7C enhances the expression of mutant p53 target genes in ovarian cancer cells. Primary ovarian carcinomas that sustain low levels of BCL7C often show the elevated expression of mutant p53 target genes. In line with these results, BCL7C abrogates mutant p53-induced cell proliferation and invasion, but had no impact on proliferation and invasion of cancer cells with depleted p53 or harboring wild-type p53. Altogether, our results demonstrate that BCL7C can act as a tumor suppressor to prevent ovarian tumorigenesis and progression by counteracting mutant p53 activity.展开更多
The deltex family protein DTX3 is believed to possess E3 ubiquitin ligase activity,as it contains a classic RING finger domain.However,its biological role and the underlying mechanism in cancer remain largely elusive....The deltex family protein DTX3 is believed to possess E3 ubiquitin ligase activity,as it contains a classic RING finger domain.However,its biological role and the underlying mechanism in cancer remain largely elusive.Here,we identified DTX3 as a novel mutant p53-interacting protein in ovarian carcinoma.Mechanistically,DTX3 mediated mutant p53 ubiqui-tination and stabilization by perturbing the MDM2-mutant p53 interaction,consequently leading to activation of diverse.mutant p53 target genes.Importantly,a positive correlation between the expression of DTX3 and mutant p53 target genes was further validated in ovarian carcinomas.Ectopic DTX3 promoted,while depletion of DTX3 suppressed,ovarian cancer cell proliferation and invasion.Remarkably,the pro-tumorigenic effect of DTX3 is dependent on mutant p53,because ablation of mutant p53 significantly impaired DTX3-induced gene expression and ovarian cancer cell growth and propagation.Furthermore,DTX3 elevated the expressi on of muta nt p53 target genes and boosted ovarian tumor growth in vivo.Fin ally,DTX3 was amplified and overexpressed in ovarian carci no mas,which is sign ificantly associated with unfavorable prognosis.Altogether,our findings unveil the oncogenic role of DTX3 in ovarian cancer development by bolstering mutant p53 activity.展开更多
Approximately half of all cancers have p53 inactivating mutations,in addition to which most malignancies inactivate the p53 pathway by increasing p53 inhibitors,decreasing p53 activators,or inactivating p53 downstream...Approximately half of all cancers have p53 inactivating mutations,in addition to which most malignancies inactivate the p53 pathway by increasing p53 inhibitors,decreasing p53 activators,or inactivating p53 downstream targets.A growing number of researches have demonstrated that p53 can influence tumor progression through the tumor microenvironment(TME).TME is involved in the process of tumor development and metastasis and affects the clinical prognosis of patients.p53 participates in host immunity and engages in the immune landscape of the TME,but the specific mechanisms remain to be investigated.This review briefly explores the interactions between different states of p53 and TME components and their mechanisms,as well as their effects on tumor progression.To understand the progress of drug development and clinical studies related to p53 and tumor microenvironment.展开更多
TP53 is a tumor suppressor gene that is mutated in most cancer types and has been extensively studied in cancer research.p53 plays a critical role in regulating the expression of target genes and is involved in key pr...TP53 is a tumor suppressor gene that is mutated in most cancer types and has been extensively studied in cancer research.p53 plays a critical role in regulating the expression of target genes and is involved in key processes such as apoptosis,cell cycle regulation,and genomic stability,earning it the title“guardian of the genome.”Numerous studies have demonstrated p53’s influence on and regulation of autophagy,ferroptosis,the tumor microenvironment,and cell metabolism,all of which contribute to tumor suppression.Alterations in p53,specifically mutant p53(mutp53),not only impair its tumor-suppressing functions but also enhance oncogenic characteristics.Recent data indicate that mutp53 is strongly associated with poor prognosis and advanced cancers,making it an ideal target for the development of novel cancer therapies.This review summarizes the post-translational modifications of p53,the mechanisms of mutp53 accumulation,and its gain-of-function,based on previous findings.Additionally,this review discusses its impact on metabolic homeostasis,ferroptosis,genomic instability,the tumor microenvironment,and cancer stem cells,and highlights recent advancements in mutp53 research.展开更多
目的探讨具有GTPase结构域、锚蛋白重复序列和PH结构域2的ADP核糖基化因子GAP(with GTPase domain,Anchor protein repeats and ArfGAP of PH domain 2,AGAP2)、离子型谷氨酸受体(Glutamate ionotropic receptor AMPA type subunit 2,GR...目的探讨具有GTPase结构域、锚蛋白重复序列和PH结构域2的ADP核糖基化因子GAP(with GTPase domain,Anchor protein repeats and ArfGAP of PH domain 2,AGAP2)、离子型谷氨酸受体(Glutamate ionotropic receptor AMPA type subunit 2,GRIA2)、代谢型谷氨酸受体结合蛋白(glutamate receptor interacting protein 1,GRIP1)和WNT信号通路中的MCC基因在肿瘤蛋白p53野生型与突变型结直肠癌中的表达差异,并评估其对细胞生物学行为的影响,尤其是AGAP2在p53突变型结直肠癌中的作用机制。方法收集p53野生型和突变型结直肠癌及癌旁组织样本,采用qRT-PCR、Western blot检测AGAP2、GRIA2、GRIP1、MCC表达;通过生物信息学分析AGAP2与GRIA2、GRIP1和MCC的蛋白相互作用,并利用免疫共沉淀技术进行验证;p53突变型结直肠癌细胞株HT29和SW480中敲除AGAP2后用CCK-8检测细胞增殖、Transwell检测侵袭能力,谷胱甘肽(glutathione,GSH)、谷胱甘肽过氧化物酶(glutathione peroxidase,GPX)活力、自由基、Fe 2+检测铁死亡指标。结果与癌旁组织比较,在p53野生型和突变型结直肠癌组织中AGAP2、GRIA2、GRIP1的mRNA和蛋白表达水平均显著上调,而MCC表达显著下调;生物信息学分析表明,AGAP2与GRIA2、GRIP1及MCC具有相互作用,并通过免疫共沉淀实验得到了验证;p53突变型结直肠癌细胞株HT-29和SW480中敲除AGAP2后,CCK-8检测细胞增殖显著降低、Transwell检测侵袭能力受到抑制,铁死亡指标检测发现:细胞中GSH、GPX活力、GPX4蛋白水平均下调,但自由基水平和Fe 2+浓度均显著上调。结论AGAP2在p53突变型结直肠癌中的高表达可能通过调控GRIA2、GRIP1及MCC促进癌细胞的恶性行为。展开更多
文摘AIM:To investigate the role of FAT10 and mutant p53 in the pathogenesis,severity and prognosis of gastric cancer.METHODS:FAT10,mutant p53 mRNA and protein levels were measured by reverse transcription(RT)-PCR and immunohistochemistry in gastric cancer tissue(n = 62),tumoradjacent tissue(n = 62) and normal gastric tissue(n = 62).Relation of FAT10 and mutant p53 expression with clinicopathological features and clinical outcomes of gastric cancer patients were analyzed.RESULTS:The FAT10,mutant p53 mRNA and protein levels were signif icantly higher in gastric cancer than in its adjacent and normal tissue.The FAT10 and mutant p53 levels in gastric cancer tissue were significantly correlated with lymph node metastasis and tumor,nodes,metastasis(TNM) staging.Moreover,the high FAT10 level was associated with the overall survival rate of patients.Multivariate Cox-proportional hazards model analysis showed that mRNA and protein levels of FAT10 and mutant p53,lymph node metastasis,distant metastasis and TNM stage were the independent prognostic factors for gastric cancer.CONCLUSION:FAT10 may be involved in gastric carcinogenesis,and is a potential marker for the prognosis of gastric cancer patients.FAT10 and mutant p53 may play a common role in the carcinogenesis of gastric cancer.
文摘Objective To investigate the role of mutated mismatch repair gene hMSH2 and mutant p53 gene in the carcinogenesis and development of sporadic digestive tract tumors. Methods hMSH2 gene in normal and tumor tissue of 30 digestive tract tumor specimens was examined using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) silver staining. The PCR product with an abnormal strand was sequenced directly. Mutant p53 protein in the tumor tissue was analyzed immunohistochemically. Results Six patients were identified as having mutated strands, three on hMSH2 exon 1 and three on hMSH2 exon 5. DNA sequencing revealed that all 6 patients had mutated basic groups that led to decrease in function of the hMSH2 protein. Forty percent (12/30) of patients were p53 positive. The frequency of mutated hMSH2 in p53 positive patients (41.7%) was significantly higher than in p53 negative patients (5.6%, P<0.05). Conclusion The mutation of hMSH2 plays an important role in the carcinogenesis and development of digestive tract tumors through stimulating p53 mutation.
基金supported by the National Program on Key Basic Research Project(2015CB901402)the National Natural Science Foundation of China(91629103,31670882, 81471066,81261120555,81672883,81401837,31071875,31200878, 31100946)+1 种基金the Science and Technology Commission of Shanghai Municipality(14430712100,11ZR1410000,16ZR1410000,16QA1401500)the Applied Basic Research Program of Science and Technology Department of Sichuan Province(2015JY0038)
文摘The tumor suppressor p53 protein is either lost or mutated in about half of all human cancers.Loss of p53 function is well known to influence cell spreading,migration and invasion.While expression of mutant p53 is not equivalent to p53 loss,mutant p53 can acquire new functions to drive cell spreading and migration via different mechanisms.In our study,we found that mutant p53 significantly increased cell spreading and migration when comparing with p53-null cells.RNA-Seq analysis suggested that Rho GTPase activating protein 44(ARHGAP44) is a new target of mutant p53,which suppressed AKHGAP44 transcription.ARHGAP44 has GAP activity and catalyze GTP hydrolysis on Cdc42.Higher level of GTP-Cdc42 was correlated with increase expression of mutant p53 and reduced ARHGAP44.Importantly,wt-ARHGAP44 but not mutant ARHGAP44(R291A) suppressed mutant p53 mediated cell spreading and migration.Bioinformatics analysis indicated lower expression of ARHGAP44 in lung carcinoma compared with normal tissues,which was verified by RT-qPCR using specimens from patients.More interestingly,ARHGAP44 mRNA level was lower in tumors with mutant p53 than those with normal p53.Collectively,our results disclose a new mechanism by which mutant p53 stimulates cell spreading and migration.
基金X.Z.was supported by the National Natural ScienceFoundation of China(81672566 and 81874053)Q.H.was sup-ported by the National Natural Science Foundation of China(81702352)Y.Z.was supported by the Natural ScienceFoundation of Hunan Province of China(2018J6059).
文摘B-cell CLL/lymphoma 7 protein family member C (BCL7C) located at chromosome 16p11.2 shares partial sequence homology with the other two family members, BCL7A and BCL7B. Its role in cancer remains completely unknown. Here, we report our finding of its tumor-suppressive role in ovarian cancer. Supporting this is that BCL7C is downregulated in human ovarian carcinomas, and its underexpression is associated with unfavorable prognosis of ovarian cancer as well as some other types of human cancers. Also, ectopic BCL7C restrains cell proliferation and invasion of ovarian cancer cells. Consistently, depletion of BCL7C reduces apoptosis and promotes cell proliferation and invasion of these cancer cells. Mechanistically, BCL7C suppresses mutant p53-mediated gene transcription by binding to mutant p53, while knockdown of BCL7C enhances the expression of mutant p53 target genes in ovarian cancer cells. Primary ovarian carcinomas that sustain low levels of BCL7C often show the elevated expression of mutant p53 target genes. In line with these results, BCL7C abrogates mutant p53-induced cell proliferation and invasion, but had no impact on proliferation and invasion of cancer cells with depleted p53 or harboring wild-type p53. Altogether, our results demonstrate that BCL7C can act as a tumor suppressor to prevent ovarian tumorigenesis and progression by counteracting mutant p53 activity.
基金This study was supported by the National Natural Science Foundation of China(No.81672566,81874053,81972431,and 81702352)the Basic and Clinical Translational Research Fundi ng from Fudan University Sha nghai Cancer Center.
文摘The deltex family protein DTX3 is believed to possess E3 ubiquitin ligase activity,as it contains a classic RING finger domain.However,its biological role and the underlying mechanism in cancer remain largely elusive.Here,we identified DTX3 as a novel mutant p53-interacting protein in ovarian carcinoma.Mechanistically,DTX3 mediated mutant p53 ubiqui-tination and stabilization by perturbing the MDM2-mutant p53 interaction,consequently leading to activation of diverse.mutant p53 target genes.Importantly,a positive correlation between the expression of DTX3 and mutant p53 target genes was further validated in ovarian carcinomas.Ectopic DTX3 promoted,while depletion of DTX3 suppressed,ovarian cancer cell proliferation and invasion.Remarkably,the pro-tumorigenic effect of DTX3 is dependent on mutant p53,because ablation of mutant p53 significantly impaired DTX3-induced gene expression and ovarian cancer cell growth and propagation.Furthermore,DTX3 elevated the expressi on of muta nt p53 target genes and boosted ovarian tumor growth in vivo.Fin ally,DTX3 was amplified and overexpressed in ovarian carci no mas,which is sign ificantly associated with unfavorable prognosis.Altogether,our findings unveil the oncogenic role of DTX3 in ovarian cancer development by bolstering mutant p53 activity.
基金supported by the Natural Science Foundation of Hunan Province(No.2021JJ30589)Hunan Provincial Natural Science Foundation Sector Joint Fund(No.2023JJ60049).
文摘Approximately half of all cancers have p53 inactivating mutations,in addition to which most malignancies inactivate the p53 pathway by increasing p53 inhibitors,decreasing p53 activators,or inactivating p53 downstream targets.A growing number of researches have demonstrated that p53 can influence tumor progression through the tumor microenvironment(TME).TME is involved in the process of tumor development and metastasis and affects the clinical prognosis of patients.p53 participates in host immunity and engages in the immune landscape of the TME,but the specific mechanisms remain to be investigated.This review briefly explores the interactions between different states of p53 and TME components and their mechanisms,as well as their effects on tumor progression.To understand the progress of drug development and clinical studies related to p53 and tumor microenvironment.
文摘TP53 is a tumor suppressor gene that is mutated in most cancer types and has been extensively studied in cancer research.p53 plays a critical role in regulating the expression of target genes and is involved in key processes such as apoptosis,cell cycle regulation,and genomic stability,earning it the title“guardian of the genome.”Numerous studies have demonstrated p53’s influence on and regulation of autophagy,ferroptosis,the tumor microenvironment,and cell metabolism,all of which contribute to tumor suppression.Alterations in p53,specifically mutant p53(mutp53),not only impair its tumor-suppressing functions but also enhance oncogenic characteristics.Recent data indicate that mutp53 is strongly associated with poor prognosis and advanced cancers,making it an ideal target for the development of novel cancer therapies.This review summarizes the post-translational modifications of p53,the mechanisms of mutp53 accumulation,and its gain-of-function,based on previous findings.Additionally,this review discusses its impact on metabolic homeostasis,ferroptosis,genomic instability,the tumor microenvironment,and cancer stem cells,and highlights recent advancements in mutp53 research.
文摘目的探讨具有GTPase结构域、锚蛋白重复序列和PH结构域2的ADP核糖基化因子GAP(with GTPase domain,Anchor protein repeats and ArfGAP of PH domain 2,AGAP2)、离子型谷氨酸受体(Glutamate ionotropic receptor AMPA type subunit 2,GRIA2)、代谢型谷氨酸受体结合蛋白(glutamate receptor interacting protein 1,GRIP1)和WNT信号通路中的MCC基因在肿瘤蛋白p53野生型与突变型结直肠癌中的表达差异,并评估其对细胞生物学行为的影响,尤其是AGAP2在p53突变型结直肠癌中的作用机制。方法收集p53野生型和突变型结直肠癌及癌旁组织样本,采用qRT-PCR、Western blot检测AGAP2、GRIA2、GRIP1、MCC表达;通过生物信息学分析AGAP2与GRIA2、GRIP1和MCC的蛋白相互作用,并利用免疫共沉淀技术进行验证;p53突变型结直肠癌细胞株HT29和SW480中敲除AGAP2后用CCK-8检测细胞增殖、Transwell检测侵袭能力,谷胱甘肽(glutathione,GSH)、谷胱甘肽过氧化物酶(glutathione peroxidase,GPX)活力、自由基、Fe 2+检测铁死亡指标。结果与癌旁组织比较,在p53野生型和突变型结直肠癌组织中AGAP2、GRIA2、GRIP1的mRNA和蛋白表达水平均显著上调,而MCC表达显著下调;生物信息学分析表明,AGAP2与GRIA2、GRIP1及MCC具有相互作用,并通过免疫共沉淀实验得到了验证;p53突变型结直肠癌细胞株HT-29和SW480中敲除AGAP2后,CCK-8检测细胞增殖显著降低、Transwell检测侵袭能力受到抑制,铁死亡指标检测发现:细胞中GSH、GPX活力、GPX4蛋白水平均下调,但自由基水平和Fe 2+浓度均显著上调。结论AGAP2在p53突变型结直肠癌中的高表达可能通过调控GRIA2、GRIP1及MCC促进癌细胞的恶性行为。
基金supported by the National Natural Science Foundation of China(Grant No.81001186)the Tianjin MunicipaNatural Science Foundation(Grant No.10JCYBJC14100)
