Characterization of a p53/miR-34a/CSF1R/STAT3 Feedback Loop in Colorectal CancerSummary
| Autor: | David Horst, Markus Kaller, Thomas Kirchner, Matjaz Rokavec, Xiaolong Shi, Heiko Hermeking |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Colorectal cancer Kaplan-Meier Estimate Receptor tyrosine kinase Metastasis Epigenesis Genetic 0302 clinical medicine GSEA gene set enrichment analysis miRNA microRNA TSA trichostatin A STAT3 Dox doxycycline qPCR quantitative real-time polymerase chain reaction Colectomy Original Research Feedback Physiological Proctectomy Gastroenterology EMT Prognosis mRNA messenger RNA 5-aza 5-aza-2’-deoxycytidine Gene Expression Regulation Neoplastic CMS consensus molecular subtype Receptors Granulocyte-Macrophage Colony-Stimulating Factor DNA methylation CRC colorectal cancer 030211 gastroenterology & hepatology TAM tumor-associated macrophage Female Fluorouracil RTK receptor tyrosine kinase EMT epithelial-mesenchymal transition Colorectal Neoplasms Chemoresistance STAT3 Transcription Factor Epithelial-Mesenchymal Transition Colon Biology 03 medical and health sciences cDNA complementary DNA Cell Line Tumor microRNA medicine COAD colon adenocarcinoma Humans 5-FU lcsh:RC799-869 Transcription factor CRIS colorectal cancer intrinsic subtype PDX patient-derived xenograft Hepatology VIM vimentin Rectum DNA Methylation medicine.disease IL interleukin MicroRNAs 030104 developmental biology Tumor progression siRNA small interfering RNA Drug Resistance Neoplasm Cancer research biology.protein Tumor Progression TCGA The Cancer Genome Atlas 5-FU 5-fluorouracil CpG Islands lcsh:Diseases of the digestive system. Gastroenterology EMT-TF epithelial-mesenchymal transition–inducing transcription factor Tumor Suppressor Protein p53 CSF1R colony-stimulating factor 1 receptor MSP methylation-specific polymerase chain reaction |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 10, Iss 2, Pp 391-418 (2020) Cellular and Molecular Gastroenterology and Hepatology |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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