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

Targeting MiRNAs for Cancer Therapy

MiRNAs could be targeted in therapy against cancer because these small molecules can play significant roles in triggering cancerous cells. Altering the expression of miRNAs might be a useful strategy in anticancer treatment.[90,91] For oncogenic miRNAs such as miR-221/-222, the purpose of intervention is to decrease or inhibit their expression. Anti-miRs have been developed as a new therapeutic approach for deactivation of these miRNAs.

Anti-miRs use different modifications to achieve good cellular uptake, good efficiency, and high stability in cancer cells. The modification includes 2′O-me, 2′O-MOE, 2′F, RNA with phosphorothioate (PS) linkage, RNA with phosphodiester (PO) linkage, RNA with cholesterol (Chol) linkage, and LNA. Another strategy in miRNA-based cancer therapy is named miRNA sponge. MiRNA sponge, which contains multiple binding sites for miRNA, joins to a vector with a strong promoter. After internalization into target cells, miRNA sponge will transcript simultaneously with the vector components. High levels of these transcripts could strongly inhibit miRNA function.

Recently, miRNA zipper, an inhibitor of miRNA, was introduced; it is a promising approach in cancer treatment.[92,93] The comparison of miRNA-221 inhibitors in terms of delivery method, properties, and function are presented in Table 3. Also, Table 4 compares the effects of Fl-Rpep-peptide nucleic acid (PNA)–anti-miR-221 and Fl-PNA-anti-miR-221 on miR-221 inhibition. Despite that advances has been made in miRNA-based therapy in cancer, this therapy is still in its beginning steps, and any restrictions must be resolved before this type of therapy can be used in clinics.

In a research, the dual luciferase reporter assay demonstrated PTEN to be a target gene of miR-221/-222. It was also illustrated that miR-221/-222 inhibition through transfection with a miR-221/-222 sponge in vitro resulted in upregulation of PTEN. We were surprised to discover that the proliferation and invasiveness of the miR-221/-222 sponge-transfected cells was considerably suppressed, and that apoptosis was elevated.[94]

Also, detection of viral vector activity in HCC cells illustrated their ability to diminish miR-221 endogenous levels, which was accompanied by promotion in CDKN1B/p27 protein, a known target of miR-221. The diminution of oncogenic miRNAs demonstrates a potential anticancer manner that identified novel miR-221 sponge vectors, which can decrease miR-221 activity regarding in vitro and in vivo delivery.[95]

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