Τίτλος:
Epigenetic regulation of miR-21 in colorectal cancer: ITGB4 as a novel miR-21 target and a three-gene network (miR-21-ITGB44-PCDC4) as predictor of metastatic tumor potential
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Previous studies have uncovered several transcription factors that determine biological alterations in tumor cells to execute the invasion-metastasis cascade, including the epithelial-mesenchymal transition (EMT). We sought to investigate the role of miR-21 in colorectal cancer regulation. For this purpose, miR-21 expression was quantified in a panel of colorectal cancer cell lines and clinical specimens. High expression was found in cell lines with EMT properties and in the vast majority of human tumor specimens. We demonstrate in a cell-specific manner the occupancy of MIR-21 gene promoter by AP-1 and ETS1 transcription factors and, for the first time, the pattern of histone posttranslational modifications necessary for miR-21 overexpression. We also show that Integrin-β4 (ITGβ4), exclusively expressed in polarized epithelial cells, is a novel miR-21 target gene and plays a role in the regulation of EMT, since it is remarkably de-repressed after transient miR-21 silencing and downregulated after miR-21 overexpression. miR-21-dependent change of ITGβ4 expression significantly affects cell migration properties of colon cancer cells. Finally, in a subgroup of tumor specimens, ROC curve analysis performed on quantitative PCR data sets for miR-21, ITGβ4, and PDCD4 shows that the combination of high miR-21 with low ITGβ4 and PDCD4 expression is able to predict presence of metastasis. In conclusion, miR-21 is a key player in oncogenic EMT, its overexpression is controlled by the cooperation of genetic and epigenetic alterations, and its levels, along with ITGβ4 and PDCD4 expression, could be exploited as a prognostic tool for CRC metastasis. © 2014 Landes Bioscience.
Συγγραφείς:
Ferraro, A.
Kontos, C.K.
Boni, T.
Bantounas, I.
Siakouli, D.
Kosmidou, V.
Vlassi, M.
Spyridakis, Y.
Tsipras, I.
Zografos, G.
Pintzas, A.
Περιοδικό:
Medical Epigenetics
Εκδότης:
Taylor and Francis Inc.
Λέξεις-κλειδιά:
beta4 integrin; membrane protein; microRNA 21; programmed cell death 4 protein; small interfering RNA; transcription factor AP 1; transcription factor Ets 1; unclassified drug; apoptosis regulatory protein; beta4 integrin; ETS1 protein, human; histone; ITGB4 protein, human; microRNA; MIRN21 microRNA, human; PDCD4 protein, human; RNA binding protein; transcription factor AP 1; transcription factor Ets 1; tumor marker, article; cancer prognosis; cell invasion; cell migration; chromatin immunoprecipitation; colorectal cancer; controlled study; DNA transfection; epigenetics; epithelial mesenchymal transition; gene expression; gene targeting; histone modification; human; human cell; human tissue; immunofluorescence test; metastasis potential; promoter region; receiver operating characteristic; reverse transcription polymerase chain reaction; sensitivity and specificity; Western blotting; colorectal tumor; gene regulatory network; genetic epigenesis; genetics; metabolism; metastasis; pathology; protein processing; tumor cell line, Apoptosis Regulatory Proteins; Biomarkers, Tumor; Cell Line, Tumor; Colorectal Neoplasms; Epigenesis, Genetic; Epithelial-Mesenchymal Transition; Gene Regulatory Networks; Histones; Humans; Integrin beta4; MicroRNAs; Neoplasm Metastasis; Protein Processing, Post-Translational; Proto-Oncogene Protein c-ets-1; RNA-Binding Proteins; Transcription Factor AP-1
