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

Epigenetics, MiR-221/-222, and Human Cancers

miRNAs have the ability to regulate genes involved in epigenetic pathways. DNA methyltransferase (DNMT) and histone modifiers, such as polycomb complex genes and histone deacetylase (HDAC), are 2 main group of epigenetic mediators.[82,83] Table 2 refers to epigenetic modifiers that are regulated by miR-221 and/or miR-222. The recent report by Lopes et al,[84] which analyzed the expression profiles of miR-21, miR-221, miR-135b, and miR-29c in noncancerous, tumor-adjacent, and tissue specimens infected with OSCC, indicated the existence of the field cancerization result in oral tumorigenesis via an epigenetic approach. Therefore, these miRNAs have the potential of representing biomarkers for detecting field cancerization of oral cancer and contributing to pathogenic procedures, along with OSCC progression.

The results of another study[85] identified that miR-221 and miR-222 can act as regulators of the functional reprogramming of macrophages during lipopolysaccharide tolerization. Enhanced stimulation with lipopolysaccharide in mice leads to promoted expression of miR-221 and mir-222, both of which adjust Brahma-related gene 1 (BRG1, also known as Smarca4). This result promoted expression triggers the transcriptional blocking of a subset of inflammatory genes that depend on chromatin remodeling mediated by switch/sucrose nonfermentable (SWI/SNF) and STAT, which in turn elevates tolerance.

Another report[86] illustrated that HMGB1, which is released via defective cells and cancer cells, overexpressed miR-221/-222 oncogenic clusters in human neuroblastoma–derived cell lines, indicated that the oncogenic cluster miR-221/-222 were expressed more extremely by the most undifferentiated cell line SK-N-BE (2), compared with the less-tumorigenic cell line SH-SY5Y, and that exogenous HMGB1 promotes this expression. Also, HMGB1 triggers PTEN expression through miR-221/-222, as identified through transiently blocking miR-221/-222 with antisense oligonucleotides. Yet another report[17] stated that the upregulation of miR-221 stimulated stem-like cells in luminal type of cancer, and the miR-221 level was associated with clinical result in patients with breast cancer, inducing EMT through upregulation of miR-221 in healthy cells and cells infected with breast cancer. The EMT-relevant gene ataxin 1 (ATXN1) was detected to be a miR-221 target gene regulating breast-cell hierarchy. Thus, miR-221 plays an important role in the lineage homeostasis of healthy epithelial cells and those infected with invasive breast cancer.