title: MiR-30a-5p suppresses tumor growth in colon carcinoma by targeting DTL.
abstract: MicroRNAs (miRNAs) are small non-coding RNAs that are involved in different biological processes by suppressing target gene expression. Altered expression of miR-30a-5p has been reported in colon carcinoma. To elucidate its potential biological role in colon cancer, miR-30a-5p was overexpressed via a lentiviral vector system in two different colon cancer cell lines. This induced in both lines miR-30a-5p-mediated growth inhibition, attributable to a cell cycle arrest at the G(1) phase and an induction of apoptosis. Combining global gene expression analyses of miR-30a-5p transgenic line HCT116 with in silico miRNA target prediction, we identified the denticleless protein homolog (DTL) as a potential miRNA-30a-5p target. Subsequent reporter gene assays confirmed the predicted miR-30a-5p binding site in the 3'untranslated region of DTL. Importantly, overexpression of DTL in HCT116 cells partially rescued these cells from miR-30a-5p-mediated growth suppression. In addition, TP53 and CDKN1A expression were increased in miR-30a-5p-overexpressing HCT116 cells, suggesting that miR-30a-5p is able to modulate the cell cycle via a DTL-TP53-CDKN1A regulatory circuit. Finally, 379 colorectal cancer tissues were screened for DTL expression and DTL was found to be overexpressed in 95.8% of human colorectal cancers compared with normal colon mucosa. In conclusion, our data identified miR-30a-5p as a tumor-suppressing miRNA in colon cancer cells exerting its function via modulation of DTL expression, which is frequently overexpressed in colorectal cancer. Thus, our data suggest that restoring miR-30a-5p function may prove useful as therapeutic strategy for tumors with reduced miR-30a-5p expression.
authors.affiliation: Molecular GI-Oncology, Center of Clinical Research, Ruhr-University Bochum, 44780 Bochum, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Baraniskin
authors.forename: Karin
authors.initials: K
authors.lastname: Birkenkamp-Demtroder
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Maghnouj
authors.forename: Hannah
authors.initials: H
authors.lastname: Zöllner
authors.forename: Johanna
authors.initials: J
authors.lastname: Munding
authors.forename: Susanne
authors.initials: S
authors.lastname: Klein-Scory
authors.forename: Anke
authors.initials: A
authors.lastname: Reinacher-Schick
authors.forename: Irmgard
authors.initials: I
authors.lastname: Schwarte-Waldhoff
authors.forename: Wolff
authors.initials: W
authors.lastname: Schmiegel
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Hahn
mesh_terms: D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D020869:Gene Expression Profiling; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C429530:DTL protein, human; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D044767:Ubiquitin-Protein Ligases