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

Disclosures

Lab Med. 2019;50(4):333-347. 

In This Article

Induction of Tumor-cell Invasion and Metastasis by MiR-221/-222

Metastasis can be defined as a complex and multistage procedure for which the epithelial-mesenchymal transition (EMT) is considered an important biological step during metastasis. Within the EMT, epithelial cells lose their cellular adhesions and represent the mesenchymal phenotype.[60,61] Some studies[62–64] reported that the expression of miR-221/-222 is associated with invasive characteristic and metastasis events in human cancers. Figure 3B refers to the mechanisms through which miR-221/-222 modulates EMT in breast cancer.

Figure 3.

Regulation mechanism of miR-221/222 and EMT progression in breast cancer. A, A model of regulating miR-221/-222 in breast cancer. The RAS-RAF–mitogen-activated protein kinase kinase (MEK)–FOS-like 1 activator protein 1 transcription factor subunit (FOSL1) signaling axis regulates the way miR-221 and miR-222 are expressed. FOSL1 heterodimerizes with a member of the JUN family to build the activator protein 1 (AP-1) complex. There is an AP-1 binding region, 12 kb upstream of miR-221/-222. FOSL1 is a positive regulator of these microRNAs. B, The mechanisms through which these microRNAs modulate the EMT in BC. MiR-221/-222 is targeted by transcriptional repressor GATA binding 1 (TRPS1), the inhibition of zinc finger E-box-binding homeobox 2 (ZEB2) by TRPS1 is removed, and ZEB2 is released and promotes EMT. MiR-221/-222 also induces EMT by targeting adiponectin receptor 1 (ADIPOR1). ADIPOR1 regulates nuclear factor kappa B (NFκβ), interleukin 6 (IL-6), JAK2/signal transducer and activator of transcription (STAT3) pathway to suppress EMT in BC.

The findings of a study by Stinson et al[12] indicated that EMT increased through miR-221 and miR-222 via transcriptional repressor GATA binding 1 (TRPS1) in breast carcinoma. In general, TRPS1 is classified in the GATA family and is an EMT inhibitor; this gene can block EMT by downregulating zinc finger E-box-binding homeobox 2 (ZEB2); thus, TRPS1 knockdown resulted in an increase in ZEB2. Up regulation of ZEB2 decreases E-cadherin abundance and increases vimentin levels to promote the EMT phenotype. These researchers treated MCF10A cells with entities that mimicked miR-221/-222; subsequently, they measured the abundance of E-cadherin and vimentin. A decline was observed in E-cadherin as an epithelial marker, and a rise was reported in vimentin as a marker of mesenchymal transition. Also, mesenchymal to epithelial transition (MET) phenotypes were created from inhibition of miR-221/-222 by anti–miR-221 and anti–miR-222. Therefore, the researchers showed that the expression of miR-221/-222 is associated with EMT markers and phenotypes.

Also, Hwang et al[15] discovered another mechanism through which miR-221/-222 can regulate the EMT in breast cancer. They identified adiponectin receptor 1 (ADIPOR1) as a target of miR-221/-222 that inhibits the EMT process and reported that ADIPOR1 can negatively regulate nuclear factor kappa beta (NFκβ), interleukin 6 (IL-6), and JAK2/STAT3 pathways to suppress EMT in breast cancer.

In another work of research, Li et al[16] evaluated the influence of miR-221/-222 on how cells invade or migrate to other tissues. They treated basal-like MDA-MB-231 cells with entities that mimicked miR-221/-222 and also performed wound-healing migration and transwell invasion assay. The results showed that wound healing and invasion were increased in these cells. The authors also treated noninvasive luminal MCF-7 cells with entities that mimic miR-221/-222; however, the aforementioned results were not observed. Anti-miR-221/-222 were treated in 3 BLBC cell lines—MDA-MB-231, SUM159, and Hs578t—then, a migration and invasion assay was applied. The results illustrated that wound closure and invasion were reduced in all 3 cell lines. In addition, the MTT assay clarified that MDA-MB-231 growth could be prevented by miR-221/-222 inhibitors.

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