Frequent activation of phosphatidylinositol-3 kinases(PI3K)/Akt/m TOR signaling pathway in gastric cancer(GC) is gaining immense popularity with identification of mutations and/or amplifications of PIK3 CA gene or los...Frequent activation of phosphatidylinositol-3 kinases(PI3K)/Akt/m TOR signaling pathway in gastric cancer(GC) is gaining immense popularity with identification of mutations and/or amplifications of PIK3 CA gene or loss of function of PTEN,a tumor suppressor protein,to name a few; both playing a crucial role in regulating this pathway. These aberrations result in dysregulation of this pathway eventually leading to gastric oncogenesis,hence,there is a need for targeted therapy for more effective anticancer treatment. Several inhibitors are currently in either preclinical or clinical stages for treatment of solid tumors like GC. With so many inhibitors under development,further studies on predictive biomarkers are needed to measure the specificity of any therapeutic intervention. Herein,we review the common dysregulation of PI3K/Akt/m TOR pathway in GC and the various types of single or dual pathway inhibitors under development that might have a superior role in GC treatment. We also summarize the recent developments in identification of predictive biomarkers and propose use of predictive biomarkers to facilitate more personalized cancer therapy with effective PI3K/Akt/m TOR pathway inhibition.展开更多
AIM:To determine how the oncogene mi R-21 regulates the RAS signaling pathways and affects colon cancer cell behaviors.METHODS:RAS p21 GTPase activating protein 1(RASA1) protein expression in six colon cancer cell lin...AIM:To determine how the oncogene mi R-21 regulates the RAS signaling pathways and affects colon cancer cell behaviors.METHODS:RAS p21 GTPase activating protein 1(RASA1) protein expression in six colon cancer cell lines was assessed by Western blot.Colon cancer RKO cells were chosen for transfection because they are KRAS wild type colon cancer cells whose RASA1 expression is significantly decreased.RKO cells were transfected with vectors overexpressing or downregulating either mi R-21 or RASA1.Furthermore,a luciferase reporter assay was used to determine whether RASA1 is a gene target of mi R-21.Then,changes in m RNA and protein levels of RASA1,RASGTP,and other components of the RAS signaling pathways were assessed in transfected RKO cells by real-time quantitative reverse transcription-polymerase chain reaction,Western blot and immunoprecipitation.Finally,cell proliferation,apoptosis,invasion,and tumorformation ability w ere assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye assay,flow cytometry,transwell assay,and animal experiment,respectively.RESULTS:RASA1 protein levels were significantly decreased in RKO cells compared with the other 5 colon cancer cell lines,and RASA1 was confirmed as a target gene of mi R-21.Interestingly,RASA1 m RNA and protein levels in pre-mi R-21-LV(up-regulation of mi R-21) cells were lower than those in anti-mi R-21-LV(down-regulation of mi R-21) cells(P < 0.05).In addition,pre-mi R-21-LV or si RASA1(down-regulation of RASA1) cells showed higher cell proliferation,reduced apoptosis,increased expression of RAS-GTP,p-AKT,Raf-1,KRAS,and p-ERK1/2,and higher invasion and tumor formation ability,compared with control,antimi R-21-LV or pc DNA3.1-RASA1(up-regulation of RASA1) cells(P < 0.05).CONCLUSION:RASA1 is a target gene of mi R-21,which promotes malignant behaviors of RKO cells through regulation of RASA1 expression.展开更多
Background:To explore and predict the mechanism of classic ancient prescription of Chinese medicine Zhen-Wu decoction for chronic heart failure treatment based on network pharmacology.Methods:Traditional Chinese medic...Background:To explore and predict the mechanism of classic ancient prescription of Chinese medicine Zhen-Wu decoction for chronic heart failure treatment based on network pharmacology.Methods:Traditional Chinese medicine systems pharmacology database was used to search the effective components and targets of herbs in classic ancient prescription of Chinese medicine Zhen-Wu decoction.Relevant target genes of chronic heart failure were obtained from GeneCards and Online Mendelian Inheritance in Man databases.Then we obtained the intersection target genes of classic ancient prescription of Chinese medicine Zhen-Wu decoction in treating chronic heart failure,constructing the classic ancient prescription of Chinese medicine Zhen-Wu decoction-active ingredient-chronic heart failure-targets network using Cytoscape,and performing network analysis using a network ananlyzer plug-in to acquire hub compounds and key targets.Proton pump inhibitor network was constructed through STRING database.Gene ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were carried out in Database for Annotation,Visualization and Integrated Discovery.Results:There are 61 active ingredients and 134 action targets in classic ancient prescription of Chinese medicine Zhen-Wu decoction,among which 49 target genes and 11 important compounds related to the chronic heart failure treatment.After network analysis,we obtained 12 key targets,77 gene ontology entries and 22 signal pathways,including tumor necrosis factor signaling pathway,NF-kappaB signal pathway,PI3K-Akt signal pathway,et al.Concludion:classic ancient prescription of Chinese medicine Zhen-Wu decoction was used for chronic heart failure treatment for the multi-component,multi-target and multi-channel interaction.The components such as kaempferol andβ-sitosterol were combined with target proteins such as CHRM1 and AChE,involving biological processes such as DNA transcription regulation,cholinergic synaptic transmission and apoptosis regulation,as well as signal pathways such as tumor necrosis factor signaling pathway,NF-kappaB signal pathway,PI3K-Akt signal pathway,et al.展开更多
基金Supported by National Medical Research Council IRG and NUHS Bench-to-Bedside grants(to Sethi G)grants from the National Medical Research Council of Singapore(R-713-000-177-511)+1 种基金the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative to Cancer Science Institute of SingaporeNational University of Singapore and by the NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust(to Kumar AP)
文摘Frequent activation of phosphatidylinositol-3 kinases(PI3K)/Akt/m TOR signaling pathway in gastric cancer(GC) is gaining immense popularity with identification of mutations and/or amplifications of PIK3 CA gene or loss of function of PTEN,a tumor suppressor protein,to name a few; both playing a crucial role in regulating this pathway. These aberrations result in dysregulation of this pathway eventually leading to gastric oncogenesis,hence,there is a need for targeted therapy for more effective anticancer treatment. Several inhibitors are currently in either preclinical or clinical stages for treatment of solid tumors like GC. With so many inhibitors under development,further studies on predictive biomarkers are needed to measure the specificity of any therapeutic intervention. Herein,we review the common dysregulation of PI3K/Akt/m TOR pathway in GC and the various types of single or dual pathway inhibitors under development that might have a superior role in GC treatment. We also summarize the recent developments in identification of predictive biomarkers and propose use of predictive biomarkers to facilitate more personalized cancer therapy with effective PI3K/Akt/m TOR pathway inhibition.
基金Supported by National Natural Science Foundation of China,No.81272770Grants from Guangdong Natural Science Foundation,No.S2013020012746Foundation of Guangdong Provincial Department of Science and Technology,No.2012A030400018
文摘AIM:To determine how the oncogene mi R-21 regulates the RAS signaling pathways and affects colon cancer cell behaviors.METHODS:RAS p21 GTPase activating protein 1(RASA1) protein expression in six colon cancer cell lines was assessed by Western blot.Colon cancer RKO cells were chosen for transfection because they are KRAS wild type colon cancer cells whose RASA1 expression is significantly decreased.RKO cells were transfected with vectors overexpressing or downregulating either mi R-21 or RASA1.Furthermore,a luciferase reporter assay was used to determine whether RASA1 is a gene target of mi R-21.Then,changes in m RNA and protein levels of RASA1,RASGTP,and other components of the RAS signaling pathways were assessed in transfected RKO cells by real-time quantitative reverse transcription-polymerase chain reaction,Western blot and immunoprecipitation.Finally,cell proliferation,apoptosis,invasion,and tumorformation ability w ere assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye assay,flow cytometry,transwell assay,and animal experiment,respectively.RESULTS:RASA1 protein levels were significantly decreased in RKO cells compared with the other 5 colon cancer cell lines,and RASA1 was confirmed as a target gene of mi R-21.Interestingly,RASA1 m RNA and protein levels in pre-mi R-21-LV(up-regulation of mi R-21) cells were lower than those in anti-mi R-21-LV(down-regulation of mi R-21) cells(P < 0.05).In addition,pre-mi R-21-LV or si RASA1(down-regulation of RASA1) cells showed higher cell proliferation,reduced apoptosis,increased expression of RAS-GTP,p-AKT,Raf-1,KRAS,and p-ERK1/2,and higher invasion and tumor formation ability,compared with control,antimi R-21-LV or pc DNA3.1-RASA1(up-regulation of RASA1) cells(P < 0.05).CONCLUSION:RASA1 is a target gene of mi R-21,which promotes malignant behaviors of RKO cells through regulation of RASA1 expression.
文摘Background:To explore and predict the mechanism of classic ancient prescription of Chinese medicine Zhen-Wu decoction for chronic heart failure treatment based on network pharmacology.Methods:Traditional Chinese medicine systems pharmacology database was used to search the effective components and targets of herbs in classic ancient prescription of Chinese medicine Zhen-Wu decoction.Relevant target genes of chronic heart failure were obtained from GeneCards and Online Mendelian Inheritance in Man databases.Then we obtained the intersection target genes of classic ancient prescription of Chinese medicine Zhen-Wu decoction in treating chronic heart failure,constructing the classic ancient prescription of Chinese medicine Zhen-Wu decoction-active ingredient-chronic heart failure-targets network using Cytoscape,and performing network analysis using a network ananlyzer plug-in to acquire hub compounds and key targets.Proton pump inhibitor network was constructed through STRING database.Gene ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were carried out in Database for Annotation,Visualization and Integrated Discovery.Results:There are 61 active ingredients and 134 action targets in classic ancient prescription of Chinese medicine Zhen-Wu decoction,among which 49 target genes and 11 important compounds related to the chronic heart failure treatment.After network analysis,we obtained 12 key targets,77 gene ontology entries and 22 signal pathways,including tumor necrosis factor signaling pathway,NF-kappaB signal pathway,PI3K-Akt signal pathway,et al.Concludion:classic ancient prescription of Chinese medicine Zhen-Wu decoction was used for chronic heart failure treatment for the multi-component,multi-target and multi-channel interaction.The components such as kaempferol andβ-sitosterol were combined with target proteins such as CHRM1 and AChE,involving biological processes such as DNA transcription regulation,cholinergic synaptic transmission and apoptosis regulation,as well as signal pathways such as tumor necrosis factor signaling pathway,NF-kappaB signal pathway,PI3K-Akt signal pathway,et al.
