MicroRNA-221 and MicroRNA-222 in Common Human Cancers

Expression, Function, and Triggering of Tumor Progression as a Key Modulator

Sima Amini, MSc; Atefe Abak, MSc; Ebrahim Sakhinia, PhD; Alireza Abhari, PhD


Lab Med. 2019;50(4):333-347. 

In This Article

Abstract and Introduction


MicroRNAs (miRNAs) are a class of short (~22 nucleotides [nt]), single-stranded RNA oligonucleotides that are regulatory in nature and are often dysregulated in various diseases, including cancer. miRNAs can act as oncomiRs (miRNAs associated with cancer) or tumor suppressor miRNAs and have the potential to be a diagnostic, prognostic, noninvasive biomarker for these diseases. MicroRNA-221 (miR-221) and microRNA-222 (miR-222) are homologous miRNAs, located on the human chromosome Xp11.3, which factored significantly in impairment in the regulation of a wide range of cancers. In this review, we have highlighted the most consistently reported dysregulated miRNAs that trigger human tissues to express cancerous features and surveyed the role of those miRNAs in metastasis, apoptosis, angiogenesis, and tumor prognosis. Also, we applied the causes of drug resistance and the role of coordinated actions of these miRNAs to epigenetic changes and selected miRNAs as a potential type of cancer treatment.


MicroRNAs (MiRNAs) are a class of small (19–25 nucleotides [nt] in length) single-stranded, noncoding RNA sequences that play central roles in modulating key biological processes by adjusting the posttranscriptional regulation of gene expression through base pairing with the complementary sequences in the 3′ untranslated region (3′-UTR) of their target messenger RNAs (mRNAs). We note that miRNAs are aberrantly expressed within cancerous tissues and can be detected in biological body fluids containing serum, plasma, and urine.[1,2] The great interest in the scientific community regarding miRNAs reflects their central role in the regulation of numerous biological and pathological procedures, including proliferation, differentiation, development, metastasis, invasion, and apoptosis.

One-third of eukaryotic genes are directly regulated through these noncoding RNAs. Also, half of human miRNA genes are situated in susceptible regions against cancer, emphasizing their significant role in tumor expansion. Thus, the anomalous expression of miRNAs can be a sign of multiple diseases, including cancers.[3–7]

Figure 1 indicates the biogenesis of miRNAs, which contains the maturation of miRNA precursors, assembly of the mature miRNA into microprocessor complexes, and the adjustment of expression of protein-coding genes by destroying or blocking translation of mRNA targets, which can be a complex procedure. Similar to other human genes, miRNA is transcribed through RNA polymerase II in the nucleus. The next stage is the generation of a precursor microRNA (pre-miRNA) through the ribonuclease (RNase) III Drosha enzyme and the processing of the double-stranded DNA-binding protein DeGeorge Critical Region 8 (DGCR8) in the nucleus; then, it is transported to the cytoplasm by Exportin 5.[8,9] In the following sequence, pre-miRNA is processed in the miRNA duplex (~18–25 nt) by the activity of the RNase III endonuclease Dicer protein. One strand of this duplex is matured miRNA that forms a complex with Argonaute proteins, called RNA-induced silencing complex (RISC).

Figure 1.

The biogenesis of microRNAs (miRNAs). Primary miRNA cleaved to precursor miRNA (~60–70 nucleotides [nt]) by RNase III endonuclease Drosha in the nucleus. It is transported to the cytoplasm by Exportin5. Precursor microRNA (pre-miRNA) is processed in miRNA duplex (~22 nt) through the activity of the Dicer enzyme. One strand of this duplex is mature miRNA that forms a complex with Argonaute proteins, called RNA-induced silencing complex (RISC). Also, messenger RNA (mRNA) decay is caused by a complete linkage between miRNA and the target mRNA, and the process of translation is hindered by partial base matching.

Finally, mRNA decay is caused by a complete linkage between miRNA and the target mRNA; also, the process of translation is hindered by partial base matching.[5,10,11] MiRNAs have a notable role in triggering all biologic processes. Also, because a single miRNA can target hundreds of mRNAs, improper miRNA expression contributes to the progression of many diseases that involve human cancers.

In this review, we focused on the most systematically reported dysregulation of microRNA-221 (miR-221) and microRNA-222 (miRNA-222) in multiple kinds of human tissues, which trigger those cells to develop cancerous features. By reviewing the results of recent studies, we evaluated the represented essential contribution of miR-221/-222 to tumorigenesis and cancer progression. In Table 1, we show data regarding the role of miR-221/-222 and the target genes of those entitites in various cell lines and cancerous tissues.