miR221/222 in cancer: their role in tumor progression and response to therapy

Abstract

miRNAs are small non-coding RNAs of ~24 nt that can block mRNA translation and/or negatively regulate its stability. There is a large body of evidence that dysregulation of miRNAs is a hallmark of cancer. miRNAs are often aberrantly expressed and their function is linked to the regulation of oncogenes and/or tumor suppressor genes involved in cell signaling pathway. miR-221 and miR-222 are two highly homologous microRNAs, whose upregulation has been recently described in several types of human tumors. miR-221/222 have been considered to act as oncogenes or tumor suppressors, depending on tumor system. Silencing oncomiRs or gene therapy approaches, based on re-expression of miRNAs that are down-regulated in cancer cells, could represent a novel anti-tumor approach for integrated cancer therapy. Here we will review the role of miR-221/222 in cancer progression and their use as prognostic and therapeutic tools in cancer.

Fig. (1). microRNA biogenesis

The production of microRNAs (miRNAs) from pri-miRNA is a complex and coordinated process operated by different groups of enzymes and associated proteins in the nucleus or cytoplasm. The pri-miRNA, located in the nucleus, is converted in pre-miRNA through the cleavage activity of the Drosha enzyme. The produced pre-miRNA is exported to the cytoplasm by the Exportin 5. Upon its arrival into the cytoplasm, the pre-miRNA is processed in ~18–22-nucleotide miRNA duplexes by the cytoplasmic RNase-III Dicer. Usually, one strand of this duplex is degraded, whereas the other strand accumulates as a mature miRNA. From the miRNA-miRNA duplex, only the miRNA enters preferentially in the protein effector complex, formed by the RNA-induced silencing complex (RISC). Perfect or nearly perfect complementarities between miRNA and its target 3’ UTR induce RISC to cleave the target mRNA, whereas imperfect base matching induces mainly translational silencing of the target.

Fig. (2). MiR-221/222 as oncomiRs

MiR-221/222 act as oncomiRs by targeting important tumor suppressor genes such as PTEN, TIMP3, p27^Kip1, p57, Bim. MiR-221/222 overexpression induces cell proliferation through the activation of cell cycle and the Akt pathway and blocks TRAIL-induced apoptosis. Moreover, miR-221/222 determine fulvestrant resistance through the activation of the β-catenin pathway.

Fig. (3). MiR-221/222 as tumor suppressor miRs

MiR-221/222 act as tumor suppressor mIRs in the erythropoietic lineage cells, and oral tongue squamous cells by targeting c-Kit, matrix metalloproteinase 1 (MMP1) and manganese superoxide dismutase (SOD2).