title: The over-expression of miR-34a fails to block DoHH2 lymphoma cell proliferation by reducing p53 via c-MYC down-regulation.
abstract: MicroRNAs (miRNAs) might behave as tumor suppressors and for that they are under consideration as novel therapeutic drugs. We tested the tumor suppressor activity of miRNA-34a (miR-34a) by measuring cell proliferation of the follicular lymphoma cell line DoHH2 transfected with this miRNA. We report that miR-34a did not inhibit cell proliferation notwithstanding a marked down-regulation of c-MYC. Interestingly, DoHH2 transfected cells showed a significant p53 down-regulation, suggesting that c-MYC positively controls p53 and the failed inhibition of cell proliferation is probably due to the down-regulation of the c-MYC/p53 axis. In keeping with this, c-MYC silencing also down-regulated p53 and had no effect on cell proliferation. In accordance with this hypothesis, etoposide or nutlin-3 treatment or a small interfering RNA (siRNA) against BCL6 (B-cell lymphoma 6) inhibited the proliferation of DoHH2 cells by up-regulating p53 without affecting either miR-34a or c-MYC levels. These results indicate that the proliferation is controlled by the regulatory axis c-MYC/p53 and suggest that paradoxically miR-34a behaves as a pro-proliferative rather than an anti-proliferative miRNA in DoHH2 cells.
authors: Laboratory of Gene and Molecular Therapy, Institute of Clinical Physiology, CNR, Pisa, Italy.
authors: Milena
authors: M
authors: Rizzo
authors: Laura
authors: L
authors: Mariani
authors: Sara
authors: S
authors: Cavallini
authors: Marcella
authors: M
authors: Simili
authors: Giuseppe
authors: G
authors: Rainaldi
mesh_terms: D020413:3' Untranslated Regions; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D005047:Etoposide / Q000494:pharmacology; D015870:Gene Expression; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008223:Lymphoma; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D000972:Antineoplastic Agents, Phytogenic; C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D007093:Imidazoles; C522425:MIRN34 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D010879:Piperazines; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C482205:nutlin 3; D005047:Etoposide