Objective:Partitioning defective protein 3(Par3)has recently been found to have important roles in cancer progression.Interestingly,Par3's functions vary among cancers:both Par3 elevation(in the prostate or liver)...Objective:Partitioning defective protein 3(Par3)has recently been found to have important roles in cancer progression.Interestingly,Par3's functions vary among cancers:both Par3 elevation(in the prostate or liver)and loss(in the breast or lung)have been implicated in cancer metastasis.Although Par3 overexpression has been correlated with diminished survival in renal cell carcinoma(RCC),data indicating the role of Par3 in RCC metastasis are lacking.Given reports of interactions between Par3 and oncoproteins such as Yesassociated protein(YAP)/WW domain-containing transcription regulator 1(TAZ),we investigated whether Par3-mediated RCC metastasis might be due to activation of the Hippo pathway components YAP and TAZ.Methods:Par3 levels were analyzed in RCC cell lines and human RCC patient tissues by western blotting and immunohistochemical(IHC)staining,as appropriate.Co-immunoprecipitation(co-IP)and immunofluorescence studies were conducted to examine the interaction between Par3 and YAP.Quantitative PCR and luciferase assays were used to investigate the effects of Par3 on YAP target gene expression and co-transcriptional regulation.PDZ domain deletion mutants of Par3 were generated to elucidate the structural basis of the interaction between Par3 and YAP.Results:Higher Par3 levels were found in distant-organ-RCC-metastasis-derived ACHN sublines than wild type ACHN cell lines.Par3 levels were also higher in the patient tissue obtained from metastatic sites than in normal kidney and primary RCC tumor tissues.Co-IP and IHC experiments demonstrated that Par3 directly interacted and co-localized with YAP/TAZ proteins.Moreover,Par3 upregulated the transcription of YAP/TAZ downstream target genes and increased the luciferase activity of YAP/TAZ responsive elements.PDZ domain 3 in the PARD3 gene was demonstrated to be particularly important in the interactions between Par3 and YAP.Furthermore,Par3 was found to upregulate intracellular levels of YAP/TAZ molecules and promote nuclear translocation of YAP.Conclusions:Together,these results indicate the role of Par3 in RCC metastasis,via driving metastatic RCC progression by promoting the YAP/TAZ pathway.展开更多
Renal cell carcinoma(RCC)is an aggressive tumor known for its propensity to invade the inferior vena cava(IVC)into the heart.Cardiac metastasis of RCC without IVC involvement is rare.Even rarer is ventricular arrhythm...Renal cell carcinoma(RCC)is an aggressive tumor known for its propensity to invade the inferior vena cava(IVC)into the heart.Cardiac metastasis of RCC without IVC involvement is rare.Even rarer is ventricular arrhythmia as the primary manifestation of cardiac metastasis of RCC with only two cases reported.[1,2]We add to the literature the third case,the diagnosis of which was only possible with cardiac magnetic resonance(CMR).展开更多
Thrombotic thrombocytopenic purpura(TTP)is a rare and life-threatening form of thrombotic microangiopathy,primarily caused by a deficiency of ADAMTS-13 activity.Immune-related adverse events(irAEs)are autoimmune toxic...Thrombotic thrombocytopenic purpura(TTP)is a rare and life-threatening form of thrombotic microangiopathy,primarily caused by a deficiency of ADAMTS-13 activity.Immune-related adverse events(irAEs)are autoimmune toxicities mediated by the use of immune checkpoint inhibitors(ICIs).Here,the study reports a case of thrombotic thrombocytopenic purpura that developed in a patient with renal cell carcinoma and vertebral metastasis following combined treatment with Toripalimab and Pazopanib.The patient received Toripalimab in combination with Pazopanib after undergoing radical nephrectomy for right renal cell carcinoma.Five days later,a generalized erythematous rash appeared,partly confluent,accompanied by congestion and swelling of both palpebral and bulbar conjunctiva.Based on the clinical presentation and laboratory results showing thrombocytopenia and hemolytic anemia,the diagnosis of TTP was established.The condition was considered an adverse effect associated with the combination therapy of Toripalimab and Pazopanib.Plasma exchange and high-dose intravenous immunoglobulin therapy were promptly initiated.The treatment regimen was subsequently modified to Axitinib combined with radiotherapy,leading to a gradual recovery of platelet counts.This report highlights the potential risk of TTP associated with combined ICI and TKI therapy,and underscores the importance of early recognition and timely management of this potentially fatal complication.展开更多
基金supported by grants from the American Urology Association(AUA)Urology Care Foundation Research Scholar AwardKidney Cancer Research Alliance Research Grant+3 种基金Simmons Comprehensive Cancer Center(SCCC)Early-Stage Clinical Investigator AwardDedman Scholar Awardsupported by the Simmons Cancer Center’s Tissue Management Shared Resourcethe National Cancer Institute of the National Institutes of Health(grant No.P30 CA142543)。
文摘Objective:Partitioning defective protein 3(Par3)has recently been found to have important roles in cancer progression.Interestingly,Par3's functions vary among cancers:both Par3 elevation(in the prostate or liver)and loss(in the breast or lung)have been implicated in cancer metastasis.Although Par3 overexpression has been correlated with diminished survival in renal cell carcinoma(RCC),data indicating the role of Par3 in RCC metastasis are lacking.Given reports of interactions between Par3 and oncoproteins such as Yesassociated protein(YAP)/WW domain-containing transcription regulator 1(TAZ),we investigated whether Par3-mediated RCC metastasis might be due to activation of the Hippo pathway components YAP and TAZ.Methods:Par3 levels were analyzed in RCC cell lines and human RCC patient tissues by western blotting and immunohistochemical(IHC)staining,as appropriate.Co-immunoprecipitation(co-IP)and immunofluorescence studies were conducted to examine the interaction between Par3 and YAP.Quantitative PCR and luciferase assays were used to investigate the effects of Par3 on YAP target gene expression and co-transcriptional regulation.PDZ domain deletion mutants of Par3 were generated to elucidate the structural basis of the interaction between Par3 and YAP.Results:Higher Par3 levels were found in distant-organ-RCC-metastasis-derived ACHN sublines than wild type ACHN cell lines.Par3 levels were also higher in the patient tissue obtained from metastatic sites than in normal kidney and primary RCC tumor tissues.Co-IP and IHC experiments demonstrated that Par3 directly interacted and co-localized with YAP/TAZ proteins.Moreover,Par3 upregulated the transcription of YAP/TAZ downstream target genes and increased the luciferase activity of YAP/TAZ responsive elements.PDZ domain 3 in the PARD3 gene was demonstrated to be particularly important in the interactions between Par3 and YAP.Furthermore,Par3 was found to upregulate intracellular levels of YAP/TAZ molecules and promote nuclear translocation of YAP.Conclusions:Together,these results indicate the role of Par3 in RCC metastasis,via driving metastatic RCC progression by promoting the YAP/TAZ pathway.
文摘Renal cell carcinoma(RCC)is an aggressive tumor known for its propensity to invade the inferior vena cava(IVC)into the heart.Cardiac metastasis of RCC without IVC involvement is rare.Even rarer is ventricular arrhythmia as the primary manifestation of cardiac metastasis of RCC with only two cases reported.[1,2]We add to the literature the third case,the diagnosis of which was only possible with cardiac magnetic resonance(CMR).
基金Natural Science Foundation of Gansu Province(Project No.:24JRRA615)Outstanding Talent Recruitment Program and the Doctoral Start-up Fund of Gansu Provincial Central Hospital(Project No.:GMCCH2024-2-6)。
文摘Thrombotic thrombocytopenic purpura(TTP)is a rare and life-threatening form of thrombotic microangiopathy,primarily caused by a deficiency of ADAMTS-13 activity.Immune-related adverse events(irAEs)are autoimmune toxicities mediated by the use of immune checkpoint inhibitors(ICIs).Here,the study reports a case of thrombotic thrombocytopenic purpura that developed in a patient with renal cell carcinoma and vertebral metastasis following combined treatment with Toripalimab and Pazopanib.The patient received Toripalimab in combination with Pazopanib after undergoing radical nephrectomy for right renal cell carcinoma.Five days later,a generalized erythematous rash appeared,partly confluent,accompanied by congestion and swelling of both palpebral and bulbar conjunctiva.Based on the clinical presentation and laboratory results showing thrombocytopenia and hemolytic anemia,the diagnosis of TTP was established.The condition was considered an adverse effect associated with the combination therapy of Toripalimab and Pazopanib.Plasma exchange and high-dose intravenous immunoglobulin therapy were promptly initiated.The treatment regimen was subsequently modified to Axitinib combined with radiotherapy,leading to a gradual recovery of platelet counts.This report highlights the potential risk of TTP associated with combined ICI and TKI therapy,and underscores the importance of early recognition and timely management of this potentially fatal complication.
