Characterization of a p53/miR-34a/CSF1R/STAT3 Feedback Loop in Colorectal CancerSummary
Background & Aims: The miR-34a gene is a direct target of p53 and is commonly silenced in colorectal cancer (CRC). Here we identified the receptor tyrosine kinase CSF1R as a direct miR-34a target and characterized CSF1R as an effector of p53/miR-34a-mediated CRC suppression. Methods: Analyse...
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| Format: | Article |
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Elsevier
2020-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X20300461 |
| _version_ | 1818035823743860736 |
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| author | Xiaolong Shi Markus Kaller Matjaz Rokavec Thomas Kirchner David Horst Heiko Hermeking |
| author_facet | Xiaolong Shi Markus Kaller Matjaz Rokavec Thomas Kirchner David Horst Heiko Hermeking |
| author_sort | Xiaolong Shi |
| collection | DOAJ |
| description | Background & Aims: The miR-34a gene is a direct target of p53 and is commonly silenced in colorectal cancer (CRC). Here we identified the receptor tyrosine kinase CSF1R as a direct miR-34a target and characterized CSF1R as an effector of p53/miR-34a-mediated CRC suppression. Methods: Analyses of TCGA-COAD and three other CRC cohorts for association of mRNA expression and signatures with patient survival and molecular subtypes. Bioinformatics identification and experimental validation of miRNA and transcription factor targets. Functional analysis of factors/pathways in the regulation of epithelial-mesenchymal transition (EMT), invasion, migration, acquired chemo-resistance and metastasis. Analyses of protein expression and CpG methylation within primary human colon cancer samples. Results: In primary CRCs increased CSF1R, CSF1 and IL34 expression was associated with poor patient survival and a mesenchymal-like subtype. CSF1R displayed an inverse correlation with miR-34a expression. This was explained by direct inhibition of CSF1R by miR-34a. Furthermore, p53 repressed CSF1R via inducing miR-34a, whereas SNAIL induced CSF1R both directly and indirectly via repressing miR-34a in a coherent feed-forward loop. Activation of CSF1R induced EMT, migration, invasion and metastasis of CRC cells via STAT3-mediated down-regulation of miR-34a. 5-FU resistance of CRC cells was mediated by CpG-methylation of miR-34a and the resulting elevated expression of CSF1R. In primary CRCs elevated expression of CSF1R was detected at the tumor invasion front and was associated with CpG methylation of the miR-34a promoter as well as distant metastasis. Conclusions: The reciprocal inhibition between miR-34a and CSF1R and its loss in tumor cells may be relevant for therapeutic and prognostic approaches towards CRC management. |
| first_indexed | 2024-12-10T07:01:11Z |
| format | Article |
| id | doaj.art-52278c3e5115469e9f3f4a23f8d6d48f |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-10T07:01:11Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-52278c3e5115469e9f3f4a23f8d6d48f2022-12-22T01:58:18ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2020-01-01102391418Characterization of a p53/miR-34a/CSF1R/STAT3 Feedback Loop in Colorectal CancerSummaryXiaolong Shi0Markus Kaller1Matjaz Rokavec2Thomas Kirchner3David Horst4Heiko Hermeking5Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, GermanyExperimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, GermanyExperimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, GermanyInstitute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany; German Cancer Consortium, Partner site Munich, Munich, Germany; German Cancer Research Center, Heidelberg, GermanyInstitute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany; German Cancer Research Center, Heidelberg, Germany; Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany; German Cancer Consortium, Partner site Berlin, Berlin, GermanyExperimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany; German Cancer Consortium, Partner site Munich, Munich, Germany; German Cancer Research Center, Heidelberg, Germany; Correspondence Address requests for reprints to: Heiko Hermeking, Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Thalkirchner Strasse 36, D-80337 Munich, Germany; fax: +49-89-2180-73697.Background & Aims: The miR-34a gene is a direct target of p53 and is commonly silenced in colorectal cancer (CRC). Here we identified the receptor tyrosine kinase CSF1R as a direct miR-34a target and characterized CSF1R as an effector of p53/miR-34a-mediated CRC suppression. Methods: Analyses of TCGA-COAD and three other CRC cohorts for association of mRNA expression and signatures with patient survival and molecular subtypes. Bioinformatics identification and experimental validation of miRNA and transcription factor targets. Functional analysis of factors/pathways in the regulation of epithelial-mesenchymal transition (EMT), invasion, migration, acquired chemo-resistance and metastasis. Analyses of protein expression and CpG methylation within primary human colon cancer samples. Results: In primary CRCs increased CSF1R, CSF1 and IL34 expression was associated with poor patient survival and a mesenchymal-like subtype. CSF1R displayed an inverse correlation with miR-34a expression. This was explained by direct inhibition of CSF1R by miR-34a. Furthermore, p53 repressed CSF1R via inducing miR-34a, whereas SNAIL induced CSF1R both directly and indirectly via repressing miR-34a in a coherent feed-forward loop. Activation of CSF1R induced EMT, migration, invasion and metastasis of CRC cells via STAT3-mediated down-regulation of miR-34a. 5-FU resistance of CRC cells was mediated by CpG-methylation of miR-34a and the resulting elevated expression of CSF1R. In primary CRCs elevated expression of CSF1R was detected at the tumor invasion front and was associated with CpG methylation of the miR-34a promoter as well as distant metastasis. Conclusions: The reciprocal inhibition between miR-34a and CSF1R and its loss in tumor cells may be relevant for therapeutic and prognostic approaches towards CRC management.http://www.sciencedirect.com/science/article/pii/S2352345X20300461EMTMetastasisChemoresistance5-FUTumor ProgressionMicroRNAs |
| spellingShingle | Xiaolong Shi Markus Kaller Matjaz Rokavec Thomas Kirchner David Horst Heiko Hermeking Characterization of a p53/miR-34a/CSF1R/STAT3 Feedback Loop in Colorectal CancerSummary Cellular and Molecular Gastroenterology and Hepatology EMT Metastasis Chemoresistance 5-FU Tumor Progression MicroRNAs |
| title | Characterization of a p53/miR-34a/CSF1R/STAT3 Feedback Loop in Colorectal CancerSummary |
| title_full | Characterization of a p53/miR-34a/CSF1R/STAT3 Feedback Loop in Colorectal CancerSummary |
| title_fullStr | Characterization of a p53/miR-34a/CSF1R/STAT3 Feedback Loop in Colorectal CancerSummary |
| title_full_unstemmed | Characterization of a p53/miR-34a/CSF1R/STAT3 Feedback Loop in Colorectal CancerSummary |
| title_short | Characterization of a p53/miR-34a/CSF1R/STAT3 Feedback Loop in Colorectal CancerSummary |
| title_sort | characterization of a p53 mir 34a csf1r stat3 feedback loop in colorectal cancersummary |
| topic | EMT Metastasis Chemoresistance 5-FU Tumor Progression MicroRNAs |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X20300461 |
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