Background:To initially clarify the potential therapeutic targets and pharmacological mechanism regarding Gualou Qumai Wan(GQW),a kind of traditional Chinese medicine(TCM),in clear cell renal cell carcinoma(ccRCC)by v...Background:To initially clarify the potential therapeutic targets and pharmacological mechanism regarding Gualou Qumai Wan(GQW),a kind of traditional Chinese medicine(TCM),in clear cell renal cell carcinoma(ccRCC)by virtue of the network pharmacology analysis and molecular docking analysis.Methods:The screening of bioactive components and targets of GQW was based on the Traditional Chinese Medicine System Pharmacology(TCMSP)and the UniProt platform served for standardizing their targets.Online Mendelian Inheritance in Man(OMIM),PharmGkb,TTD,DrugBank and GeneCards databases were searched to collect the disease targets of ccRCC.Cytoscape assisted in constructing herb-compound-target(H-C-T)networks.The STRING database was searched for constructing the target protein-protein interaction(PPI)networks,while the R programming language served for analyzing GO functional terms and the KEGG pathways related to potential targets.Analyses of core genes related to survival and tumor microenvironment(TME)were conducted respectively based on the GEPIA2 database and TIMER 2.0 database.Human Protein Atlas(HPA)and The Cancer Genome Atlas(TCGA)helped to obtain core genes’protein expression as well as transcriptome expression level.Autodock Vina software validated the molecular docking regarding GQW components and pivotal targets.Results:The constructed H-C-T networks mainly had 33 compounds and 65 targets.A topological analysis of the PPI network identified that ESR1,AKT1,HIF1A,PTGS2,TP53 and VEGFA serve as core targets in the way GQW affects ccRCC.According to the GO and KEGG pathway enrichment analyses,the effects of GQW are mediated by genes related to hypoxia and oxidative stress as well as the Chemical carcinogenesis-receptor activation and PI3K-Akt signaling pathways.AKT1 shows a close relation to the recruitment of various immune cells and can remarkably affect disease prognosis according to reports.Molecular docking and molecular dynamics simulations showed that diosgenin has higher affinity with core targets.Conclusion:The study makes a comprehensive explanation of the biological activity,potential targets,as well as molecular mechanism regarding GQW against ccRCC,which promisingly assists in revealing the action mechanism of TCM formulae in disease treatment and the respective and scientific basis.展开更多
Objective: To better understand the contribution of dysregulated DNA methyltransferase 1 (DNMT1) expression to the progression and biology of clear cell renal cell carcinoma (ccRCC). Methods: We examined the dif...Objective: To better understand the contribution of dysregulated DNA methyltransferase 1 (DNMT1) expression to the progression and biology of clear cell renal cell carcinoma (ccRCC). Methods: We examined the differences in the expression of DNMT1 in 89 ecRCC and 22 normal tissue samples by immunohistochemistry. In addition, changes in cell viability, apoptosis, colony formation and invading ability of ccRCC cell lines (786-0 and Caki-1) were assessed after transfection with DNMT1 siRNA. Results: We found DNMT1 protein was significantly higher expressed in ccRCC than that of in no-tumor tissues (56.2% and 27.3%, respectively, P=0.018). The expression of DNMT1 was strongly associated with ccRCC tumor size, tumor pathology stage, histological grading, lymph node metastasis, vascular invasion, recurrence and prognosis. Moreover, knockdown of DNMT1 expression significantly inhibited ccRCC cell viability, induced apoptosis, decreased colony formation and invading ability. Conclusions: Expression of DNMTI protein is increased in ccRCC tissues, and DNMT1 expression is associated with poor prognosis of patients. Experiments in vitro further showed DNMT1 played an essential role in proliferation and invasion of renal cancer cells. Moreover, targeting this enzyme could be a promising strategy for treating ccRCC, as evidenced by inhibited cell viability, increased apoptosis, decreased colony formation and invading ability.展开更多
Objective:To explore the expression of Netrin-1 protein in human renal clear cell carcinoma(RCCC) and the relationships between Netrin-1.pathology and prognosis.Methods:72 cases of RCCC admitted in our hospital from 2...Objective:To explore the expression of Netrin-1 protein in human renal clear cell carcinoma(RCCC) and the relationships between Netrin-1.pathology and prognosis.Methods:72 cases of RCCC admitted in our hospital from 2008 June to 2009 June and their adjacent tissues were selected for study.They included 30 cases in stage Ⅰ-Ⅱ.42 cases in stage Ⅲ-Ⅳ;9 cases in grade Ⅰ.9 cases in grade Ⅱ.40 cases in grade Ⅲ and 14 cases in grade Ⅳ.All cases were followed up for more than 5 years.Survival analysis lines were made by Kaplan—Meier method and the difference between groups was tested by the Log-rank test.The expression of Netrin-1 protein was detected by immunohistochemistry staining and its clinical significance was analyzed.Results:Renal clear cell carcinoma:51 cases in high expression of Netrin-1and 21 cases in low expression,normal tissues:12 cases in high expression of Netrin-1and 60 cases in low expression,the difference between the two groups is significant(x^2=42.921,P<0.01).The difference of the expression of Netrin-lin Fuhrman grade and AJCC clinical stage is significant(x^2=8.000.x^2=6.203:P<0.05).The 5-year survival rate in low protein expression group and in high protein expression group was 79% (17/21) and 62% (32/51).The survival curve had different trend,with no significant difference between groups(x^2=1.360.P=0.245).Conclusions:Netrin-1 protein plays an important role in the development of RCCC.It might be a new specific tumor marker of RCCC.and might become a new target in treatment of RCCC.展开更多
In this study,we used a meta-analysis method to evaluate the relationship between hypoxia-inducible factor-1α(HIF1α)1772C/T gene polymorphism(rs 11549465)and renal cell carcinoma(RCC)/prostate cancer risk.We searche...In this study,we used a meta-analysis method to evaluate the relationship between hypoxia-inducible factor-1α(HIF1α)1772C/T gene polymorphism(rs 11549465)and renal cell carcinoma(RCC)/prostate cancer risk.We searched for relevant studies(before March 1,2019)on Cochrane Library,Embase,and PubMed.Studies meeting the inclusion criteria were recruited into this meta-analysis.The outcome of dichotomous data was showed in the way of odds ratios(OR),and 95%confidence intervals(CI)were also counted.In this investigation,there was no association between HIF1α1772C/T gene polymorphism and susceptibility to RCC in Caucasians,Asians as well as overall populations.In addition,HIF1α1772C/T gene polymorphism was not found to be relevant to the survival in RCC.Interestingly,the T allele was relevant to prostate cancer risk in all populations,but not in Caucasians and Asians.However,the TT genotype and the CC genotype were not related to prostate cancer susceptibility in Asian,Caucasian,and all populations.In conclusion,the T allele of the HIF1α1772C/T gene polymorphism was related to prostate cancer risk in the overall populations.展开更多
Clear cell renal cell carcinoma(KIRC)is the most common and aggressivemalignancy subtype of renal neoplasm that arises from proximal convoluted tubules.It is characterized by poor clinical outcomes and high mortality ...Clear cell renal cell carcinoma(KIRC)is the most common and aggressivemalignancy subtype of renal neoplasm that arises from proximal convoluted tubules.It is characterized by poor clinical outcomes and high mortality of patients due to the lack of specific biomarkers for varying stages of the disease and no effective treatment.Proteases are associated with the development of several malignant tumors in humans by their ability to degrade extracellular matrices,facilitating metastasis.Herein,differentially expressed genes in KIRC cases compared to healthy kidneys were screened out from the Gene Expression Profiling Interactive Analysis(GEPIA)database.This data was applied to determine the most elevated protease in KIRC and as a result,A Disintegrin and Metalloproteinase Domain-Like Protein Decysin-1(ADAMDEC1)was selected.This expression pattern was exclusive for KIRC and not observed for papillary and chromophobe renal cell carcinomas,in which ADAMDEC1 was at the same level in tumors and non-cancer specimens.Furthermore,the ADAMDEC1 significant increase was detected in the fourteen other human malignancies compared to healthy samples,which suggested its strong involvement in cancer development.Next,GEPIA and Pathology Atlas correlated ADAMDEC1 high expression with more advanced tumor grade and shorter survival of KIRC patients.Xena Functional Genomics Explorer presented that ADAMDEC1 could be hypermethylated in some tumor cases and one somatic mutation in the gene sequence was detected.Finally,a Search Tool for the Retrieval of Interacting Genes/Proteins;STRING base was utilized to predict the interactions of ADAMDEC1 with other molecules and construct the signaling network.In summary,ADAMDEC1 showed the tremendous potential to be the predictive marker for the KIRC and its development.Therefore,this review with data analysis can be a good base for further in vitro and in vivo research that experimentally can confirm the ADAMDEC1 as prognostic biomarkers and therapeutic target of KIRC.展开更多
Objective:To explore the anti-tumor of breast cancer metastasis suppressor 1(BRMS1)on renal cell carcinoma.Methods:BRSM1 stabilized overexpressed and knockdown cell models were constructed to detect the effect of BRMS...Objective:To explore the anti-tumor of breast cancer metastasis suppressor 1(BRMS1)on renal cell carcinoma.Methods:BRSM1 stabilized overexpressed and knockdown cell models were constructed to detect the effect of BRMS1 overexpression and knockdown on viability rate of 769-P cells.Activation of PI3K/AKT-mTOR-NFκB signaling pathway,expression of cellular apoptosis-related proteins,DNA damage repair-related proteins and angiogenesis-related proteins were detected using Western blotting analysis.Results:The viability rate of 769-P cells were significantly decreased in BRMS1 overexpression cells while significantly increased in BRMS1 knockdown cells(P<0.05).The activity of PI3K/AKT-mTOR-NFκB signaling pathway was significantly inhibited with BRMS1 overexpression(P<0.05),and expression of BAX was significantly increased with significantly decreased expression of Bcl-2(P<0.05).Besides,BRMS1 overexpression could significantly decrease the expression of DNA damage repair-related proteins and angiogenesis and cell-matrix degradation related proteins(P<0.05).Conclusion:BRMS1 induces apoptosis of renal cell carcinoma and performs an anti-tumor effect via inhibition of PI3K/AKT-mTOR-NFκB signaling pathway,expression of DNA damage repair-related proteins and angiogenesis-related proteins.展开更多
Objective To identify the expression of DLK1 protein in different types of renal cell carcinomas and its correlations with pathological characteristics and metastasis. Methods Immunohistochemistry analysis was perform...Objective To identify the expression of DLK1 protein in different types of renal cell carcinomas and its correlations with pathological characteristics and metastasis. Methods Immunohistochemistry analysis was performed to evaluate the expression of DLK1 protein in展开更多
Background:Lymphatic metastasis is one of the most common metastatic routes and indicates a poor prognosis in clear-cell renal cell carcinoma(ccRCC).N-acetyltransferase 10(NAT10)is known to catalyze N4-acetylcytidine(...Background:Lymphatic metastasis is one of the most common metastatic routes and indicates a poor prognosis in clear-cell renal cell carcinoma(ccRCC).N-acetyltransferase 10(NAT10)is known to catalyze N4-acetylcytidine(ac4C)modification of mRNA and participate in many cellular processes.However,its role in the lymphangiogenic process of ccRCC has not been reported.This study aimed to elucidate the role of NAT10 in ccRCC lymphangiogenesis,providing valuable insights into potential therapeutic targets for intervention.Methods:ac4C modification and NAT10 expression levels in ccRCC were assessed using public databases and clinical samples.Functional investigations involved manipulating NAT10 expression in cellular and mouse models to study its role in ccRCC.Mechanistic insights were gained through a combination of RNA sequencing,mass spectrometry,co-immunoprecipitation,RNA immuno-precipitation,immunofluorescence,and site-specific mutation analyses.Results:We found that ac4C modification and NAT10 expression levels increased in ccRCC.NAT10 promoted tumor progression and lymphangiogene-sis of ccRCC by enhancing the nuclear import of Yes1-associated transcriptional regulator(YAP1).Subsequently,we identified ankyrin repeat and zinc fin-ger peptidyl tRNA hydrolase 1(ANKZF1)as the functional target of NAT10,and its upregulation in ccRCC was caused by NAT10-mediated ac4C modifi-cation.Mechanistic analyses demonstrated that ANKZF1 interacted with tyro-sine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon(YWHAE)to competitively inhibit cytoplasmic retention of YAP1,leading to transcriptional activation of pro-lymphangiogenic factors.Conclusions:These results suggested a pro-cancer role of NAT10-mediated acetylation in ccRCC and identified the NAT10/ANKZF1/YAP1 axis as an under-reported pathway involving tumor progression and lymphangiogenesis in ccRCC.展开更多
Objective Kidney renal clear cell carcinoma(KIRC)is a common renal malignancy that has a poor prognosis.As a member of the F box family,cyclin F(CCNF)plays an important regulatory role in normal tissues and tumors.How...Objective Kidney renal clear cell carcinoma(KIRC)is a common renal malignancy that has a poor prognosis.As a member of the F box family,cyclin F(CCNF)plays an important regulatory role in normal tissues and tumors.However,the underlying mechanism by which CCNF promotes KIRC proliferation still remains unclear.Methods Bioinformatics methods were used to analyze The Cancer Genome Atlas(TCGA)database to obtain gene expression and clinical prognosis data.The CCK8 assay,EdU assay,and xenograft assay were used to detect cell proliferation.The cell senescence and potential mechanism were assessed by SA-β-gal staining,Western blotting,as well as ELISA.Results Our data showed that CCNF was highly expressed in KIRC patients.Meanwhile,downregulation of CCNF inhibited cell proliferation in vivo and in vitro.Further studies showed that the reduction of CCNF promoted cell senescence by decreasing cyclin-dependent kinase 1(CDK1),increasing the proinflammatory factors interleukin(IL)-6 and IL-8,and then enhancing the expression of p21 and p53.Conclusion We propose that the high expression of CCNF in KIRC may play a key role in tumorigenesis by regulating cell senescence.Therefore,CCNF shows promise as a new biomarker to predict the clinical prognosis of KIRC patients and as an effective therapeutic target.展开更多
Renal cell carcinomas(RCC)make up about 90%of kidney cancers,of which 80%are of the clear cell subtype.About 20%of patients are already metastatic at the time of diagnosis.Initial treatment is often cytoreductive neph...Renal cell carcinomas(RCC)make up about 90%of kidney cancers,of which 80%are of the clear cell subtype.About 20%of patients are already metastatic at the time of diagnosis.Initial treatment is often cytoreductive nephrectomy,but systemic therapy is required for advanced RCC.Single agent targeted therapies are moderately toxic and only somewhat effective,leading to development of immunotherapies and combination therapies.This review identifies limitations of monotherapies for metastatic renal cell carcinoma,discusses recent advances in combination therapies,and highlights therapeutic options under development.The goal behind combining various modalities of systemic therapy is to potentiate a synergistic antitumor effect.However,combining targeted therapies may cause increased toxicity.The initial attempts to create therapeutic combinations based on inhibition of the vascular endothelial growth factor or mammalian target of rapamycin pathways were largely unsuccessful in achieving a profile of increased synergy without increased toxicity.To date,five combination therapies have been approved by the U.S.Food and Drug Administration,with the most recently approved therapies being a combination of checkpoint inhibition plus targeted therapy.Several other combination therapies are under development,including some in the phase 3 stage.The new wave of combination therapies for metastatic RCC has the potential to increase response rates and improve survival outcomes while maintaining tolerable side effect profiles.展开更多
Objective: To study the expression of dendritic cells in human renal cell carcinoma and explore the cause, so to reveal the mechanism of escaping immune surveillance in RCC. Methods: The expressions of CD83+DCS, CD1a+...Objective: To study the expression of dendritic cells in human renal cell carcinoma and explore the cause, so to reveal the mechanism of escaping immune surveillance in RCC. Methods: The expressions of CD83+DCS, CD1a+DCS,VEGF and TGF-β1 in tumoral, peritumoral and normal kidney tissues of RCC in 30 cases were detected by immunohistochemistry using streptavidin/peroxidese(SP) Results: CD83+DCS were mainly located in the peritumoral areas; whereas CD1a+DCS、were mainly retained within the cancer nests. The number of CD83+DCS was inversely correlated with the clinical stage(P<0.05); but there were no significant correlations between the number of CD1a+DCS、and the clinical stage(P>0.05). The expressions of CD83+DCS and CD1a+DCS have significant difference between the tumoral, peritumoral and normal kidney tissues(P<0.001). The expression of VEGF and TGF-β1 were significantly lower in samples with highly infiltrating CD83+DCS(P<0.05); Whereas CD1a+DCS were not (P>0.05). Conclusion: DC has the tendency to gathering in tumor, but because of the immunosuppressive cytokins, for example VEGF and TGF-β1, inhibits the maturation of DC, there are less mature TIDCS(CD83+TIDCS) in the tumoral tissues, they are mainly located in the peritumoral areas. This may contribute to the mechanism of escaping immune surveillance in RCC.展开更多
Systemic therapy for metastatic renal cell carcinoma(mRCC)has evolved drastically,with agents targeting vascular endothelial growth factor(VEGF)and the mammalian target of rapamycin(mTOR)now representing a standard of...Systemic therapy for metastatic renal cell carcinoma(mRCC)has evolved drastically,with agents targeting vascular endothelial growth factor(VEGF)and the mammalian target of rapamycin(mTOR)now representing a standard of care.The present paper is to review the current status of relevant clinical trials that were either recently completed or ongoing.(1)Though observation remains a standard of care following resection of localized disease,multiple trials are underway to assess VEGF-and mTOR-directed therapies in this setting.(2)While the preponderance of retrospective data favors cytoreductive nephrectomy in the context of targeted agents,prospective data to support this approach is still forthcoming.(3)The first-line management of mRCC may change substantially with multiple studies exploring vaccines,immune checkpoint inhibitors,and novel targeted agents currently underway.In general,prospective studies that will report within the next several years will be critical in defining the role of adjuvant therapy and cytoreductive nephrectomy.Over the same span of time,the current treatment paradigm for first-line therapy may evolve.展开更多
Renal cell cancer(RCC)represents 2%-3% of all adulthood cancers and is the most common malignant neoplasm of the kidney(90%).In the mid-nineties of the last century,the standard of treatment for patients with metastat...Renal cell cancer(RCC)represents 2%-3% of all adulthood cancers and is the most common malignant neoplasm of the kidney(90%).In the mid-nineties of the last century,the standard of treatment for patients with metastatic RCC was cytokines.Sunititib and pazopanib were registered in 2007 and 2009,respectively,and have since been the standard first-line treatment for metastatic clear cell RCC(mccRCC).Renal cell cancer is a highly immunogenic tumor with tumor infiltrating cells,including CD8+T lymphocytes,dendritic cells,natural killer cells(NK)and macrophages.This observation led to the design of new clinical trials in which patients were treated with immunotherapy.With the growing evidence that proangiogenic factors can have immunomodulatory effects on the host’s immune system,the idea of combining angiogenic drugs with immunotherapy has emerged,and new clinical trials have been designed.In the last few years,several therapeutic options have been approved[immunotherapy and immunotherapy/tyrosine kinase inhibitors(TKI)]for the first-line treatment of mccRCC.Nivolumab/ipilimumab is approved for the treatment of patients with intermediate and poor prognoses.Several checkpoint inhibitors(pembrolizumab,nivolumab,avelumab)in combination with TKI(axitinib,lenvatinib,cabozantinib)are approved for the treatment of patients regardless of their International mRCC Database Consortium prognostic group and PD-L1 expression.There is no specific and ideal biomarker that could help in selecting the ideal patient for the appropriate first-line treatment.展开更多
基金supported by Weifang Health Commission Traditional Chinese Medicine Research Project Plan(WFZYY2023-1-004).
文摘Background:To initially clarify the potential therapeutic targets and pharmacological mechanism regarding Gualou Qumai Wan(GQW),a kind of traditional Chinese medicine(TCM),in clear cell renal cell carcinoma(ccRCC)by virtue of the network pharmacology analysis and molecular docking analysis.Methods:The screening of bioactive components and targets of GQW was based on the Traditional Chinese Medicine System Pharmacology(TCMSP)and the UniProt platform served for standardizing their targets.Online Mendelian Inheritance in Man(OMIM),PharmGkb,TTD,DrugBank and GeneCards databases were searched to collect the disease targets of ccRCC.Cytoscape assisted in constructing herb-compound-target(H-C-T)networks.The STRING database was searched for constructing the target protein-protein interaction(PPI)networks,while the R programming language served for analyzing GO functional terms and the KEGG pathways related to potential targets.Analyses of core genes related to survival and tumor microenvironment(TME)were conducted respectively based on the GEPIA2 database and TIMER 2.0 database.Human Protein Atlas(HPA)and The Cancer Genome Atlas(TCGA)helped to obtain core genes’protein expression as well as transcriptome expression level.Autodock Vina software validated the molecular docking regarding GQW components and pivotal targets.Results:The constructed H-C-T networks mainly had 33 compounds and 65 targets.A topological analysis of the PPI network identified that ESR1,AKT1,HIF1A,PTGS2,TP53 and VEGFA serve as core targets in the way GQW affects ccRCC.According to the GO and KEGG pathway enrichment analyses,the effects of GQW are mediated by genes related to hypoxia and oxidative stress as well as the Chemical carcinogenesis-receptor activation and PI3K-Akt signaling pathways.AKT1 shows a close relation to the recruitment of various immune cells and can remarkably affect disease prognosis according to reports.Molecular docking and molecular dynamics simulations showed that diosgenin has higher affinity with core targets.Conclusion:The study makes a comprehensive explanation of the biological activity,potential targets,as well as molecular mechanism regarding GQW against ccRCC,which promisingly assists in revealing the action mechanism of TCM formulae in disease treatment and the respective and scientific basis.
基金supported by grants from National Natural Science Foundation of China (No. 30873097)
文摘Objective: To better understand the contribution of dysregulated DNA methyltransferase 1 (DNMT1) expression to the progression and biology of clear cell renal cell carcinoma (ccRCC). Methods: We examined the differences in the expression of DNMT1 in 89 ecRCC and 22 normal tissue samples by immunohistochemistry. In addition, changes in cell viability, apoptosis, colony formation and invading ability of ccRCC cell lines (786-0 and Caki-1) were assessed after transfection with DNMT1 siRNA. Results: We found DNMT1 protein was significantly higher expressed in ccRCC than that of in no-tumor tissues (56.2% and 27.3%, respectively, P=0.018). The expression of DNMT1 was strongly associated with ccRCC tumor size, tumor pathology stage, histological grading, lymph node metastasis, vascular invasion, recurrence and prognosis. Moreover, knockdown of DNMT1 expression significantly inhibited ccRCC cell viability, induced apoptosis, decreased colony formation and invading ability. Conclusions: Expression of DNMTI protein is increased in ccRCC tissues, and DNMT1 expression is associated with poor prognosis of patients. Experiments in vitro further showed DNMT1 played an essential role in proliferation and invasion of renal cancer cells. Moreover, targeting this enzyme could be a promising strategy for treating ccRCC, as evidenced by inhibited cell viability, increased apoptosis, decreased colony formation and invading ability.
基金supported by Sichuan Province Natural Science Foundation of China:sc271123
文摘Objective:To explore the expression of Netrin-1 protein in human renal clear cell carcinoma(RCCC) and the relationships between Netrin-1.pathology and prognosis.Methods:72 cases of RCCC admitted in our hospital from 2008 June to 2009 June and their adjacent tissues were selected for study.They included 30 cases in stage Ⅰ-Ⅱ.42 cases in stage Ⅲ-Ⅳ;9 cases in grade Ⅰ.9 cases in grade Ⅱ.40 cases in grade Ⅲ and 14 cases in grade Ⅳ.All cases were followed up for more than 5 years.Survival analysis lines were made by Kaplan—Meier method and the difference between groups was tested by the Log-rank test.The expression of Netrin-1 protein was detected by immunohistochemistry staining and its clinical significance was analyzed.Results:Renal clear cell carcinoma:51 cases in high expression of Netrin-1and 21 cases in low expression,normal tissues:12 cases in high expression of Netrin-1and 60 cases in low expression,the difference between the two groups is significant(x^2=42.921,P<0.01).The difference of the expression of Netrin-lin Fuhrman grade and AJCC clinical stage is significant(x^2=8.000.x^2=6.203:P<0.05).The 5-year survival rate in low protein expression group and in high protein expression group was 79% (17/21) and 62% (32/51).The survival curve had different trend,with no significant difference between groups(x^2=1.360.P=0.245).Conclusions:Netrin-1 protein plays an important role in the development of RCCC.It might be a new specific tumor marker of RCCC.and might become a new target in treatment of RCCC.
基金the Guangzhou Medical Key Discipline Construction Project(2017-2019)the Science and Technology Project of Shantou(Shanfuke(2019)106-4:190606165268433).
文摘In this study,we used a meta-analysis method to evaluate the relationship between hypoxia-inducible factor-1α(HIF1α)1772C/T gene polymorphism(rs 11549465)and renal cell carcinoma(RCC)/prostate cancer risk.We searched for relevant studies(before March 1,2019)on Cochrane Library,Embase,and PubMed.Studies meeting the inclusion criteria were recruited into this meta-analysis.The outcome of dichotomous data was showed in the way of odds ratios(OR),and 95%confidence intervals(CI)were also counted.In this investigation,there was no association between HIF1α1772C/T gene polymorphism and susceptibility to RCC in Caucasians,Asians as well as overall populations.In addition,HIF1α1772C/T gene polymorphism was not found to be relevant to the survival in RCC.Interestingly,the T allele was relevant to prostate cancer risk in all populations,but not in Caucasians and Asians.However,the TT genotype and the CC genotype were not related to prostate cancer susceptibility in Asian,Caucasian,and all populations.In conclusion,the T allele of the HIF1α1772C/T gene polymorphism was related to prostate cancer risk in the overall populations.
文摘Clear cell renal cell carcinoma(KIRC)is the most common and aggressivemalignancy subtype of renal neoplasm that arises from proximal convoluted tubules.It is characterized by poor clinical outcomes and high mortality of patients due to the lack of specific biomarkers for varying stages of the disease and no effective treatment.Proteases are associated with the development of several malignant tumors in humans by their ability to degrade extracellular matrices,facilitating metastasis.Herein,differentially expressed genes in KIRC cases compared to healthy kidneys were screened out from the Gene Expression Profiling Interactive Analysis(GEPIA)database.This data was applied to determine the most elevated protease in KIRC and as a result,A Disintegrin and Metalloproteinase Domain-Like Protein Decysin-1(ADAMDEC1)was selected.This expression pattern was exclusive for KIRC and not observed for papillary and chromophobe renal cell carcinomas,in which ADAMDEC1 was at the same level in tumors and non-cancer specimens.Furthermore,the ADAMDEC1 significant increase was detected in the fourteen other human malignancies compared to healthy samples,which suggested its strong involvement in cancer development.Next,GEPIA and Pathology Atlas correlated ADAMDEC1 high expression with more advanced tumor grade and shorter survival of KIRC patients.Xena Functional Genomics Explorer presented that ADAMDEC1 could be hypermethylated in some tumor cases and one somatic mutation in the gene sequence was detected.Finally,a Search Tool for the Retrieval of Interacting Genes/Proteins;STRING base was utilized to predict the interactions of ADAMDEC1 with other molecules and construct the signaling network.In summary,ADAMDEC1 showed the tremendous potential to be the predictive marker for the KIRC and its development.Therefore,this review with data analysis can be a good base for further in vitro and in vivo research that experimentally can confirm the ADAMDEC1 as prognostic biomarkers and therapeutic target of KIRC.
基金This study was supported by Tianjin Municipal Science and Technology Project(Grant No.16ZXHLSY00120).
文摘Objective:To explore the anti-tumor of breast cancer metastasis suppressor 1(BRMS1)on renal cell carcinoma.Methods:BRSM1 stabilized overexpressed and knockdown cell models were constructed to detect the effect of BRMS1 overexpression and knockdown on viability rate of 769-P cells.Activation of PI3K/AKT-mTOR-NFκB signaling pathway,expression of cellular apoptosis-related proteins,DNA damage repair-related proteins and angiogenesis-related proteins were detected using Western blotting analysis.Results:The viability rate of 769-P cells were significantly decreased in BRMS1 overexpression cells while significantly increased in BRMS1 knockdown cells(P<0.05).The activity of PI3K/AKT-mTOR-NFκB signaling pathway was significantly inhibited with BRMS1 overexpression(P<0.05),and expression of BAX was significantly increased with significantly decreased expression of Bcl-2(P<0.05).Besides,BRMS1 overexpression could significantly decrease the expression of DNA damage repair-related proteins and angiogenesis and cell-matrix degradation related proteins(P<0.05).Conclusion:BRMS1 induces apoptosis of renal cell carcinoma and performs an anti-tumor effect via inhibition of PI3K/AKT-mTOR-NFκB signaling pathway,expression of DNA damage repair-related proteins and angiogenesis-related proteins.
文摘Objective To identify the expression of DLK1 protein in different types of renal cell carcinomas and its correlations with pathological characteristics and metastasis. Methods Immunohistochemistry analysis was performed to evaluate the expression of DLK1 protein in
基金This study was supported by the National Natural Sci-ence Foundation of China(81874090,81972630,82202911,82300786).
文摘Background:Lymphatic metastasis is one of the most common metastatic routes and indicates a poor prognosis in clear-cell renal cell carcinoma(ccRCC).N-acetyltransferase 10(NAT10)is known to catalyze N4-acetylcytidine(ac4C)modification of mRNA and participate in many cellular processes.However,its role in the lymphangiogenic process of ccRCC has not been reported.This study aimed to elucidate the role of NAT10 in ccRCC lymphangiogenesis,providing valuable insights into potential therapeutic targets for intervention.Methods:ac4C modification and NAT10 expression levels in ccRCC were assessed using public databases and clinical samples.Functional investigations involved manipulating NAT10 expression in cellular and mouse models to study its role in ccRCC.Mechanistic insights were gained through a combination of RNA sequencing,mass spectrometry,co-immunoprecipitation,RNA immuno-precipitation,immunofluorescence,and site-specific mutation analyses.Results:We found that ac4C modification and NAT10 expression levels increased in ccRCC.NAT10 promoted tumor progression and lymphangiogene-sis of ccRCC by enhancing the nuclear import of Yes1-associated transcriptional regulator(YAP1).Subsequently,we identified ankyrin repeat and zinc fin-ger peptidyl tRNA hydrolase 1(ANKZF1)as the functional target of NAT10,and its upregulation in ccRCC was caused by NAT10-mediated ac4C modifi-cation.Mechanistic analyses demonstrated that ANKZF1 interacted with tyro-sine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon(YWHAE)to competitively inhibit cytoplasmic retention of YAP1,leading to transcriptional activation of pro-lymphangiogenic factors.Conclusions:These results suggested a pro-cancer role of NAT10-mediated acetylation in ccRCC and identified the NAT10/ANKZF1/YAP1 axis as an under-reported pathway involving tumor progression and lymphangiogenesis in ccRCC.
基金supported by the National Natural Science Foundation of China(No.81874148 and No.82203142).
文摘Objective Kidney renal clear cell carcinoma(KIRC)is a common renal malignancy that has a poor prognosis.As a member of the F box family,cyclin F(CCNF)plays an important regulatory role in normal tissues and tumors.However,the underlying mechanism by which CCNF promotes KIRC proliferation still remains unclear.Methods Bioinformatics methods were used to analyze The Cancer Genome Atlas(TCGA)database to obtain gene expression and clinical prognosis data.The CCK8 assay,EdU assay,and xenograft assay were used to detect cell proliferation.The cell senescence and potential mechanism were assessed by SA-β-gal staining,Western blotting,as well as ELISA.Results Our data showed that CCNF was highly expressed in KIRC patients.Meanwhile,downregulation of CCNF inhibited cell proliferation in vivo and in vitro.Further studies showed that the reduction of CCNF promoted cell senescence by decreasing cyclin-dependent kinase 1(CDK1),increasing the proinflammatory factors interleukin(IL)-6 and IL-8,and then enhancing the expression of p21 and p53.Conclusion We propose that the high expression of CCNF in KIRC may play a key role in tumorigenesis by regulating cell senescence.Therefore,CCNF shows promise as a new biomarker to predict the clinical prognosis of KIRC patients and as an effective therapeutic target.
文摘Renal cell carcinomas(RCC)make up about 90%of kidney cancers,of which 80%are of the clear cell subtype.About 20%of patients are already metastatic at the time of diagnosis.Initial treatment is often cytoreductive nephrectomy,but systemic therapy is required for advanced RCC.Single agent targeted therapies are moderately toxic and only somewhat effective,leading to development of immunotherapies and combination therapies.This review identifies limitations of monotherapies for metastatic renal cell carcinoma,discusses recent advances in combination therapies,and highlights therapeutic options under development.The goal behind combining various modalities of systemic therapy is to potentiate a synergistic antitumor effect.However,combining targeted therapies may cause increased toxicity.The initial attempts to create therapeutic combinations based on inhibition of the vascular endothelial growth factor or mammalian target of rapamycin pathways were largely unsuccessful in achieving a profile of increased synergy without increased toxicity.To date,five combination therapies have been approved by the U.S.Food and Drug Administration,with the most recently approved therapies being a combination of checkpoint inhibition plus targeted therapy.Several other combination therapies are under development,including some in the phase 3 stage.The new wave of combination therapies for metastatic RCC has the potential to increase response rates and improve survival outcomes while maintaining tolerable side effect profiles.
文摘Objective: To study the expression of dendritic cells in human renal cell carcinoma and explore the cause, so to reveal the mechanism of escaping immune surveillance in RCC. Methods: The expressions of CD83+DCS, CD1a+DCS,VEGF and TGF-β1 in tumoral, peritumoral and normal kidney tissues of RCC in 30 cases were detected by immunohistochemistry using streptavidin/peroxidese(SP) Results: CD83+DCS were mainly located in the peritumoral areas; whereas CD1a+DCS、were mainly retained within the cancer nests. The number of CD83+DCS was inversely correlated with the clinical stage(P<0.05); but there were no significant correlations between the number of CD1a+DCS、and the clinical stage(P>0.05). The expressions of CD83+DCS and CD1a+DCS have significant difference between the tumoral, peritumoral and normal kidney tissues(P<0.001). The expression of VEGF and TGF-β1 were significantly lower in samples with highly infiltrating CD83+DCS(P<0.05); Whereas CD1a+DCS were not (P>0.05). Conclusion: DC has the tendency to gathering in tumor, but because of the immunosuppressive cytokins, for example VEGF and TGF-β1, inhibits the maturation of DC, there are less mature TIDCS(CD83+TIDCS) in the tumoral tissues, they are mainly located in the peritumoral areas. This may contribute to the mechanism of escaping immune surveillance in RCC.
文摘Systemic therapy for metastatic renal cell carcinoma(mRCC)has evolved drastically,with agents targeting vascular endothelial growth factor(VEGF)and the mammalian target of rapamycin(mTOR)now representing a standard of care.The present paper is to review the current status of relevant clinical trials that were either recently completed or ongoing.(1)Though observation remains a standard of care following resection of localized disease,multiple trials are underway to assess VEGF-and mTOR-directed therapies in this setting.(2)While the preponderance of retrospective data favors cytoreductive nephrectomy in the context of targeted agents,prospective data to support this approach is still forthcoming.(3)The first-line management of mRCC may change substantially with multiple studies exploring vaccines,immune checkpoint inhibitors,and novel targeted agents currently underway.In general,prospective studies that will report within the next several years will be critical in defining the role of adjuvant therapy and cytoreductive nephrectomy.Over the same span of time,the current treatment paradigm for first-line therapy may evolve.
文摘Renal cell cancer(RCC)represents 2%-3% of all adulthood cancers and is the most common malignant neoplasm of the kidney(90%).In the mid-nineties of the last century,the standard of treatment for patients with metastatic RCC was cytokines.Sunititib and pazopanib were registered in 2007 and 2009,respectively,and have since been the standard first-line treatment for metastatic clear cell RCC(mccRCC).Renal cell cancer is a highly immunogenic tumor with tumor infiltrating cells,including CD8+T lymphocytes,dendritic cells,natural killer cells(NK)and macrophages.This observation led to the design of new clinical trials in which patients were treated with immunotherapy.With the growing evidence that proangiogenic factors can have immunomodulatory effects on the host’s immune system,the idea of combining angiogenic drugs with immunotherapy has emerged,and new clinical trials have been designed.In the last few years,several therapeutic options have been approved[immunotherapy and immunotherapy/tyrosine kinase inhibitors(TKI)]for the first-line treatment of mccRCC.Nivolumab/ipilimumab is approved for the treatment of patients with intermediate and poor prognoses.Several checkpoint inhibitors(pembrolizumab,nivolumab,avelumab)in combination with TKI(axitinib,lenvatinib,cabozantinib)are approved for the treatment of patients regardless of their International mRCC Database Consortium prognostic group and PD-L1 expression.There is no specific and ideal biomarker that could help in selecting the ideal patient for the appropriate first-line treatment.