Oncogenic MicroRNAs: Key Players in Malignant Transformation

Abstract

MicroRNAs (miRNAs) represent a class of non-coding RNAs that exert pivotal roles in the regulation of gene expression at the post-transcriptional level. MiRNAs are involved in many biological processes and slight modulations in their expression have been correlated with the occurrence of different diseases. In particular, alterations in the expression of miRNAs with oncogenic or tumor suppressor functions have been associated with carcinogenesis, malignant transformation, metastasis and response to anticancer treatments. This review will mainly focus on oncogenic miRNAs whose aberrant expression leads to malignancy.

Keywords: apoptosis; cancer; cell cycle regulation; oncogenic miRNAs.

Figure 1

Oncogenic miRNAs involved in cell cycle progression. Cell cycle is divided into four phases, G1, S, G2, and M. Regulation of the cell cycle, including the detection and repair of genetic damage, is controlled by a series of checkpoints. Cyclins and cyclin-dependent kinases (CDKs) are key proteins that determine cell progression through the different phases of cell cycle. Oncogenic miRNAs contribute to cell cycle entry and progression by targeting CDK inhibitors or tumor suppressor genes involved in cell cycle. ATM (Ataxia Telangiectasia Mutated).

Figure 2

Oncogenic miRNAs involved in the apoptotic pathway. Anti-apoptotic miRNAs exert their function in both extrinsic and intrinsic apoptotic pathways by regulating pro-apoptotic mRNAs including caspases. Caspase 3-7-9 are downregulated by miR-106b-25 cluster, miR let-7, miR-582-5p and miR-363. TRAIL ligand, involved in extrinsic pathway is downregulated by miR-22 and miR-222. Also PTEN, that promotes the formation of the Death-Inducing Signaling Complex Apoptosis, is regulated by several miRs. BCL-2 family members such as PUMA, BMF, BAX and BAK members, involved in intrinsic pathway, are downregulated by many anti-apoptotic miRNAs, which lead to resistance to apoptosis. FADD (Fas-Associated protein with Death Domain); TRAIL (TNF-Related Apoptosis-Inducing Ligand); DISC (Death-Inducing Signaling Complex); PTEN (Phosphatase and Tensin homolog); BMF (Bcl2 Modifying Factor); PUMA (BCL2 binding component 3); BIM (BCL2-like 11); BAX (BCL2-Associated X protein); BAK (BCL2-Antagonist/Killer 1).