Mir-34: a new weapon against cancer?

Abstract

The microRNA(miRNA)-34a is a key regulator of tumor suppression. It controls the expression of a plethora of target proteins involved in cell cycle, differentiation and apoptosis, and antagonizes processes that are necessary for basic cancer cell viability as well as cancer stemness, metastasis, and chemoresistance. In this review, we focus on the molecular mechanisms of miR-34a-mediated tumor suppression, giving emphasis on the main miR-34a targets, as well as on the principal regulators involved in the modulation of this miRNA. Moreover, we shed light on the miR-34a role in modulating responsiveness to chemotherapy and on the phytonutrients-mediated regulation of miR-34a expression and activity in cancer cells. Given the broad anti-oncogenic activity of miR-34a, we also discuss the substantial benefits of a new therapeutic concept based on nanotechnology delivery of miRNA mimics. In fact, the replacement of oncosuppressor miRNAs provides an effective strategy against tumor heterogeneity and the selective RNA-based delivery systems seems to be an excellent platform for a safe and effective targeting of the tumor.

Figure 1

MiR-34a biogenesis. DNA damage activates the p53 gene, that binds to the miR-34a promoter and up-regulates miRNA expression. Mutation in the DNA-binding domain of p53 negatively affects this processing, thus reducing the expression of the related miRNAs. CpG island miR-34a promoter hypermethylation induces a miR-34a silencing that is dominant over its transactivation by p53 after DNA damage. MiR-34a is originally transcribed as long hairpin molecule (pri-miRNA) that is subsequently processed by the human RNase III DROSHA, into a stem-loop precursor of approximately 70 nucleotides (pre-miRNAs). Exportin-5 mediates the miR-34a traslocation from the nucleus to the cytoplasm. Another human RNase III, DICER, through several steps, cuts miR-34a into duplexes with final 22–23nt length. As a last step, one strand of the miRNA duplex (‘‘mature strand'') is incorporated into the RNA-induced silencing complex (RISC) while the other is supposedly degraded. Once integrated into the RISC, miR34a guide this protein complex to partially or totally complementary binding sites located in the 3' untranslated region (UTR) of target mRNAs and inhibit their expression. In detail, the perfect alignment causes mRNA degradation, while the partial alignment interfers with mRNA translation.

Figure 2

Cellular outcomes associated with miR-34a-induced gene silencing. Representation of the main miR-34a target mRNAs, and biological effects associated with their repression. MiR-34a can antagonize many different oncogenic processes.