MicroRNAs, stem cells and cancer stem cells

Abstract

This review discusses the various regulatory characteristics of microRNAs that are capable of generating widespread changes in gene expression via post translational repression of many mRNA targets and control self-renewal, differentiation and division of cells. It controls the stem cell functions by controlling a wide range of pathological and physiological processes, including development, differentiation, cellular proliferation, programmed cell death, oncogenesis and metastasis. Through either mRNA cleavage or translational repression, miRNAs alter the expression of their cognate target genes; thereby modulating cellular pathways that affect the normal functions of stem cells, turning them into cancer stem cells, a likely cause of relapse in cancer patients. This present review further emphasizes the recent discoveries on the functional analysis of miRNAs in cancer metastasis and implications on miRNA based therapy using miRNA replacement or anti-miRNA technologies in specific cancer stem cells that are required to establish their efficacy in controlling tumorigenic potential and safe therapeutics.

Keywords: Cancer stem cells; Cellular pathways; Stem cell functions; Tumor suppressor miRNAs; miRNA; miRNA based therapeutics; oncomiR.

Figure 1

MiRNA biogenesis, functions and potential therapeutic targets. miRNA transcript excised to form pri-miRNA, gets cleaved by Drosha and exported from nucleus to cytoplasm by Exportin-5. 70 n hairpin-loop precursor-miRNA (pre-miRNA) then processed by Dicer into mature RNA. The figure also explains the various potential miRNA therapeutic targets including biogenic pathways, restoring the tumor suppressor functions of miRNAs and blocking the oncogenic properties of miRNAs. miRNA mediated silencing involves either inhibition of translation or degradation of their target mRNA transcripts depending on the degree of complementarity. TRBP: Transactivating response RNA binding protein; miRISC: miRNA-induced silencing complex; miRNP: MicroRNA ribonucleoprotein complex; DGCR8: DiGeorge syndrome critical region gene 8.

Figure 2

Stem cells express a unique set of miRNAs that maintain self-renewal, promote differentiation and maturation through various regulatory mechanisms. Distinct small sub population of cells arises from stem cells due to accumulation of genetic and epigenetic abnormalities that might function as cancer stem cells. These cells display differential expression of miRNAs which regulate the fundamental properties that contribute to enhanced tumor initiation and metastatic potential.