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

Impact of miR-221/-222 in Tumor Progression

Cell-cycle progression controlled by various factors, such as cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors that are broadly adjusted through these noncoding RNAs. p27, a CDK inhibitor that can suppress cell-cycle progression, has been shown[26] to be a considerable direct target of miR-221/-222. Also, Lu et al[53] found that miR-221 can promote proliferation in human glioma by targeting p27 and initiating cancerous processes in brain tissue.

Another study[54] reported that these 2 miRNAs can regulate melanoma progression by downregulation of p27/cyclin-dependent kinase inhibitor 1B (p27Kip1; also known as CDKN1B), and C-KIT target process genes. Also, a recent report[56] divulged that the inhibitory impact of miR-221 and miR-222 on p27 could be disrupted through the cytoplasmic element binding protein 1 (CPEB1) gene. CPEB1 belongs to the CPEB family, which modulates translation by attaching to the 3′UTR of mRNAs. P27 is a target of miR-221/-222 and CPEB1; unlike miRNA-221 and miRNA-222, which inhibits the expression of p27, CPEB1 encourages it. Due to the competition occuring between miRNA-221/-222 and CPEB1 on contiguity of the p27 overlapping area, the repressing mechanism of CPEB1 is specific to the tumor cells.

We were intrigued by the findings of Hsieh et al[55] that miR-221/-222 can promote tumor growth via targeting nuclear protein SUN2 in atypical teratoid (AT)/rhabdoid tumor (RT), which is a kind of central nervous system (CNS) tumor. Targeting miR-221, miR-222, and SUN2 may represent a new therapeutic strategy for AT/RT remedy. Also, Xu Q et al[57] show that these 2 miRNAs promote pancreatic cancer (PC) progression by controlling matrix metalloproteinases (MMPs). Treatment of PC with cells that mimic miR-221-/-222 leads to downregulation of TIMP metalloproteinase inhibitor-2 (TIMP2, which is the target gene of miR-221/-222) and an increase in MMP-2 and MMP-9, the two components of the MMP family that contribute to invasive characteristic of cancer.

A study by Dentelli et al found that miR-221/-222 regulates proliferation, tumor growth, and invasion in luminal-like breast cancer by targeting signal transducer and activator of transcription (STAT)5A, disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), and β4-integrin. Their results revealed that miR-221/-222 can control β4-integrin expression in luminal MCF-7 cells. Upregulation of miR-221/-222 resulted in downregulation of β4-integrin in this cell line. Downregulation of these miRNAs in MCF-10 cells did not alter β4-integrin expression. Their results revealed this mechanism is specific to tumor cells.[13]

In another report, Di Martino et al[58] investigated the antitumor activity of locked nucleic acid (LNA)–i-miR-221 in MM cells with or without t(4, 14) translocation. They proved the anti-MM function in cells carrying translocation (group A) but not in the other ones (group B), so their outcomes suggested that LNA-i-miR-221 might be useful for the treatment of group A of patients. miR-221/-222 modulates the behavior of cancer cells by regulating different target genes and some biological process in human cells. Figure 2 refers to the direct target genes of miR-221/-222.

Figure 2.

Schema summarizing of the different genes targeted by microRNA-221/-222 (miR–221/-222).