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

MiR-221/-222 as Regulators of Apoptosis Mechanisms in Cancer

Tumor cells can adopt various strategies to override apoptosis containment, amplification of the antiapoptotic machinery, downregulation of the proapoptotic program, or both of these tactics. Proapoptotic factors are widely adjusted and controlled via miRNAs. To suppress apoptosis in glioma, miR-221/-222 targets a proapoptotic gene named PUMA (p53-upregulated modulator of apoptosis).[24]

In another study, Zhang et al[18] reported that in epithelial carcinoma, miR-221/-222 targets PUMA. Their study results revealed that downregulation of miR-221/-222 by oligonucleotides increased caspase 3/7 expression and led to apoptosis in A549 and MCF-7 cells. To investigate the effect of miR-221 knockdown on apoptosis, they treated cell lines with anti–miR-221 and then measured apoptosis markers; cleaved caspase 3 and B-cell lymphoma 2–associated death (BAD) phosphorylation. They observed that downregulation of miR-221 caused an increase in cleaved caspase 3 and a decrease in B-cell lymphoma 2–associated death promoter (PBAD) in TNBC cell lines.

Also, Gramantieri et al[25] reported that there is a negative correlation between miR-221 and B-cell lymphoma 2–modifying factor (BMF) and a positive correlation between BMF and the apoptosis marker caspase-3 in HCC. They revealed that miR-221 inhibits apoptosis via inhibition of BMF in HCC. The study also identified that the upregulation of miR-221 resulted in a more aggressive phenotype in this type of malignant neoplasm.

In addition, Wang et al[66] showed a negative association between miR-221/-222 and caspase-10 by evaluating cases of prostate cancer. The results indicated that when miR-221/-222 is downregulated, the cancerous cells become sensitive to apoptosis caused by tumor necrosis factor–α/cycloheximide. In another study report,[67] researchers disclosed that the depletion of miR-221 and miR-222 could enhance the apoptosis process by modulation of phosphatase and tensin homolog (PTEN). They treated cells with an miRNA sponge and then measured the number of apoptotic cells via Annexin V/PI testing (BioLegend); their observations revealed an increase in apoptosis.