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A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma.

ABSTRACT: The p53 tumor suppressor, a central mediator of chemosensitivity in normal cells, is functionally inactivated in many human cancers. Therefore, a central challenge in human cancer therapy is the identification of pathways that control tumor cell survival and chemosensitivity in the absence of functional p53. The p53-related transcription factors p63 and p73 exhibit distinct functions—p73 mediates chemosensitivity while p63 promotes proliferation and cell survival—and are both overexpressed in squamous cell carcinomas (SCCs). However, how p63 and p73 interact functionally and govern the balance between prosurvival and proapoptotic programs in SCC remains elusive. Here, we identify a microRNA-dependent mechanism of p63/p73 crosstalk that regulates p53-independent survival of both human and murine SCC. We first discovered that a subset of p63-regulated microRNAs target p73 for inhibition. One of these, miR-193a-5p, expression of which was repressed by p63, was activated by proapoptotic p73 isoforms in both normal cells and tumor cells in vivo. Chemotherapy caused p63/p73-dependent induction of this microRNA, thereby limiting chemosensitivity due to microRNA-mediated feedback inhibition of p73. Importantly, inhibiting miR-193a interrupted this feedback and thereby suppressed tumor cell viability and induced dramatic chemosensitivity both in vitro and in vivo. Thus, we have identified a direct, microRNA-dependent regulatory circuit mediating inducible chemoresistance, whose inhibition may provide a new therapeutic opportunity in p53-deficient tumors.

SUBMITTER: Ory B

PROVIDER: S-EPMC3026726 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma.

Ory Benjamin B Ramsey Matthew R MR Wilson Catherine C Vadysirisack Douangsone D DD Forster Nicole N Rocco James W JW Rothenberg S Michael SM Ellisen Leif W LW

The Journal of clinical investigation 20110201 2

The p53 tumor suppressor, a central mediator of chemosensitivity in normal cells, is functionally inactivated in many human cancers. Therefore, a central challenge in human cancer therapy is the identification of pathways that control tumor cell survival and chemosensitivity in the absence of functional p53. The p53-related transcription factors p63 and p73 exhibit distinct functions—p73 mediates chemosensitivity while p63 promotes proliferation and cell survival—and are both overexpressed in sq ...[more]

PMID: 21293058

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Project description:OBJECTIVE: To investigate the differentially expressed genes and miRNAs related to the chemosensitivity of hypopharyngeal squamous cell carcinoma ï¼HSCCï¼by microarrays and miRNA arrays. METHODS: 1. A total number of 21 patients who underwent induction chemotherapy for primary hypopharyngeal squamous cell carcinoma (12 patients are sensitive to chemotherapy ,and others are not) were recruited for microarray and miRNA array gene expression analysis 2. Bioinformatics analysis of differentially expressed genes screened by microarrays : The differential gene cluster analysis was applied in biological processes, cellular components and molecular functions by GO database; The differential gene enrichment analysis was applied in signaling pathways by KEGG database, and the differentially expressed and biologically meaningful core genes would be screened. 3. Prediction and analysis of target genes of differentially expressed miRNAs: TargetScan, PITA and microRNAorg methods were used for target gene prediction in GeneSpring 12.5 software, and the intersection of the three methods analysis was considered as significant target genes. Considering the result of microarrays, the intersection of the predicted target genes and the genes screened by microarrays would be analyzed by bioinformatics, which were considered as genes regulated by different miRNAs. RESULTS: 1. Analyzed by microarrays, there were 1579 genes significantly related to the sensitivity to chemotherapy; Among these 1579genes, 815 showed a higher expression in the tissue from patients who are sensitive to chemotherapy , while 764 presented the contrasting pattern. 2. Analyzed by miRNA arrays, there were 24 genes significantly related to the sensitivity to chemotherapy; Among them, 6 showed a higher expression in the tissue from patients who are sensitive to chemotherapy , while 18 presented the contrasting pattern. TargetScan, PITA and microRNAorg were used for target gene prediction in GeneSpring 12.5 software, and the intersection of the three methods analysis was considered as significant target genes. There were 613 putative target genes corresponding to the 24 significant miRNAs. Among them, six genes(MAPK14, ADCY1, GSTM4, CDC42, JUN, GPX6) were statistically and biologically different related to the sensitivity to chemotherapy. And among the 24 significant miRNAs, miR-193b-3pãmiR-211-3pãmiR-4253ãmiR-4496ãmiR-6738-5p could regulate them. CONCLUSIONS: The research revealed a gene expression signature of chemosensitivity in hypopharyngeal squamous cell carcinoma by microarrays and miRNA arrays. The result will contribute to the understanding of the molecular basis of hypopharyngeal squamous cell carcinoma and help to improve diagnosis and treatment. 1. A total number of 21 patients who underwent induction chemotherapy for primary hypopharyngeal squamous cell carcinoma (12 patients are sensitive to chemotherapy ,and others are not) were recruited for microarray and miRNA array gene expression analysis 2. Bioinformatics analysis of differentially expressed genes screened by microarrays : The differential gene cluster analysis was applied in biological processes, cellular components and molecular functions by GO database; The differential gene enrichment analysis was applied in signaling pathways by KEGG database, and the differentially expressed and biologically meaningful core genes would be screened. 3. Prediction and analysis of target genes of differentially expressed miRNAs: TargetScan, PITA and microRNAorg methods were used for target gene prediction in GeneSpring 12.5 software, and the intersection of the three methods analysis was considered as significant target genes. Considering the result of microarrays, the intersection of the predicted target genes and the genes screened by microarrays would be analyzed by bioinformatics, which were considered as genes regulated by different miRNAs.

Project description:OBJECTIVE: To investigate the differentially expressed genes related to the chemosensitivity of laryngeal squamous cell carcinoma ï¼LSCCï¼by microarrays arrays. METHODS: 1. A total number of 11 patients who underwent induction chemotherapy for primary hypopharyngeal squamous cell carcinoma (7 patients are sensitive to chemotherapy ,and others are not) were recruited for microarray and miRNA array gene expression analysis 2. Bioinformatics analysis of differentially expressed genes screened by microarrays : The differential gene cluster analysis was applied in biological processes, cellular components and molecular functions by GO database; The differential gene enrichment analysis was applied in signaling pathways by KEGG database, and the differentially expressed and biologically meaningful core genes would be screened. RESULTS: 1. Analyzed by microarrays, there were 1554 genes significantly related to the sensitivity to chemotherapy; Among these 1554genes, 777 showed a higher expression in the tissue from patients who are sensitive to chemotherapy , while 785 presented the contrasting pattern. CONCLUSIONS: The research revealed a gene expression signature of chemosensitivity in laryngeal squamous cell carcinoma by microarrays arrays. The result will contribute to the understanding of the molecular basis of laryngeal squamous cell carcinoma and help to improve diagnosis and treatment. 1. A total number of 11 patients who underwent induction chemotherapy for primary hypopharyngeal squamous cell carcinoma (7 patients are sensitive to chemotherapy ,and others are not) were recruited for microarray and miRNA array gene expression analysis 2. Bioinformatics analysis of differentially expressed genes screened by microarrays : The differential gene cluster analysis was applied in biological processes, cellular components and molecular functions by GO database; The differential gene enrichment analysis was applied in signaling pathways by KEGG database, and the differentially expressed and biologically meaningful core genes would be screened.

Project description:OBJECTIVE: To investigate the differentially expressed genes and miRNAs related to the chemosensitivity of hypopharyngeal squamous cell carcinoma （HSCC）by microarrays and miRNA arrays. METHODS: 1. A total number of 21 patients who underwent induction chemotherapy for primary hypopharyngeal squamous cell carcinoma (12 patients are sensitive to chemotherapy ,and others are not) were recruited for microarray and miRNA array gene expression analysis 2. Bioinformatics analysis of differentially expressed genes screened by microarrays : The differential gene cluster analysis was applied in biological processes, cellular components and molecular functions by GO database; The differential gene enrichment analysis was applied in signaling pathways by KEGG database, and the differentially expressed and biologically meaningful core genes would be screened. 3. Prediction and analysis of target genes of differentially expressed miRNAs: TargetScan, PITA and microRNAorg methods were used for target gene prediction in GeneSpring 12.5 software, and the intersection of the three methods analysis was considered as significant target genes. Considering the result of microarrays, the intersection of the predicted target genes and the genes screened by microarrays would be analyzed by bioinformatics, which were considered as genes regulated by different miRNAs. RESULTS: 1. Analyzed by microarrays, there were 1579 genes significantly related to the sensitivity to chemotherapy; Among these 1579genes, 815 showed a higher expression in the tissue from patients who are sensitive to chemotherapy , while 764 presented the contrasting pattern. 2. Analyzed by miRNA arrays, there were 24 genes significantly related to the sensitivity to chemotherapy; Among them, 6 showed a higher expression in the tissue from patients who are sensitive to chemotherapy , while 18 presented the contrasting pattern. TargetScan, PITA and microRNAorg were used for target gene prediction in GeneSpring 12.5 software, and the intersection of the three methods analysis was considered as significant target genes. There were 613 putative target genes corresponding to the 24 significant miRNAs. Among them, six genes(MAPK14, ADCY1, GSTM4, CDC42, JUN, GPX6) were statistically and biologically different related to the sensitivity to chemotherapy. And among the 24 significant miRNAs, miR-193b-3p、miR-211-3p、miR-4253、miR-4496、miR-6738-5p could regulate them. CONCLUSIONS: The research revealed a gene expression signature of chemosensitivity in hypopharyngeal squamous cell carcinoma by microarrays and miRNA arrays. The result will contribute to the understanding of the molecular basis of hypopharyngeal squamous cell carcinoma and help to improve diagnosis and treatment.

Dataset Information

A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma.

Publications

A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma.

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