MicroRNA miR-34a is recognized as a master regulator of tumor suppression. The strategy of miR-34a replacement has been investigated in clinical trials as the first attempt of miRNA application in cancer treatment. However, emerging outcomes promote the re-evaluation of existing knowledge and urge the need for better understanding the complex biological role of miR-34a. The targets of miR-34a encompass numerous regulators of cancer cell proliferation, survival and resistance to therapy. MiR-34a expression is transcriptionally controlled by p53, a crucial tumor suppressor pathway, often disrupted in cancer. Moreover, miR-34a abundance is fine-tuned by context-dependent feedback loops. The function and effects of exogenously delivered or re-expressed miR-34a on the background of defective p53 therefore remain prominent issues in miR-34a based therapy. In this work, we review p53-independent mechanisms regulating the expression of miR-34a. Aside from molecules directly interacting with MIR34A promoter, processes affecting epigenetic regulation and miRNA maturation are discussed. Multiple mechanisms operate in the context of cancer-associated phenomena, such as aberrant oncogene signaling, EMT or inflammation. Since p53-dependent tumor-suppressive mechanisms are disturbed in a substantial proportion of malignancies, we summarize the effects of miR-34a modulation in cell and animal models in the clinically relevant context of disrupted or insufficient p53 function.

Center of Biomolecular and Cellular Engineering International Clinical Research Center St Anne's University Hospital Brno Brno Czech Republic

Department of Cytokinetics Institute of Biophysics of the Czech Academy of Sciences Brno Czech Republic

Department of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic

Division of Experimental Urology Department of Urology Medical University of Innsbruck Innsbruck Austria

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Cell Death Dis. 2018 Jul 16;9(8):783. doi: 10.1038/s41419-018-0833-1. PubMed

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