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2017 ; 8
(10
): e3100
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Alternative mechanisms of miR-34a regulation in cancer
#MMPMID29022903
Slabáková E
; Culig Z
; Rem?ík J
; Sou?ek K
Cell Death Dis
2017[Oct]; 8
(10
): e3100
PMID29022903
show ga
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.
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