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

Role of MiR-221/-222 in Causing Tumor Angiogenesis

Tumor cells can create new blood vessels to supply nutrients and oxygen, which they require for their growth and progression—this process is called angiogenesis. The angiogenic switch depends on the balance of antiangiogenic and proangiogenic factors. Some of these factors could be modified by miRNAs, and growing evidence[73–75] suggests the regulatory role of miRNAs in angiogenesis. Herein, we focus on the roles of miR-221/-222 in the angiogenesis process during tumor-cell development. Yang et al[20] reported that miR-222 promotes angiogenesis of glioma cells by targeting TIMP2, which is a member of the TIMP family. Tissue inhibitors of metalloproteinase are antiangiogenic factors that can inhibit the activity of MMPs in stopping tube formation.

miR-221/-222 can display antiangiogenic effects in endothelial cells. Also, Poliseno et al[73] indicated that miR-221/-222 regulates the angiogenic activity of the stem-cell factor (SCF) by targeting the C-KIT in human umbilical-vein endothelial cells (HUVECs). SCF is identified as a ligand for the SCF-receptor C-KIT. The coauthors observed that miR-221 and miR-222 repress capillary tube formation, wound healing, survival, and migration by downregulation of the C-KIT in HUVECs.

Upregulation of miR-221/-222 indirectly decreases endothelial nitric oxide synthase (eNOS) released in endothelial cells by Dicer knockdown. The eNOS is an enzyme that produces nitric oxide (NO) in endothelial cells. NO modulates endothelial cell growth, migration, and angiogenesis. So, miR-221/-222 acts as a repressor of angiogenesis by decreasing eNOS.[76]

In another report, Chen et al[77] state another mechanism through which miR-221 represses angiogenesis. In a study on molecular and cellular biology, they demonstrated that miR-221 upregulates GAX by downregulating ZEB2, a repressor of GAX. GAX (mesenchyme homeobox 2 [MEOX2]) is a homeobox gene that has antiangiogenic effects in endothelial cells. GAX is downregulated by ZEB2; this process occurs via attaching to 2 ZEB2/SIP1 binding sites in GAX3. The findings by Chen et al suggest that targeting ZEB2 could be used for antiangiogenic therapy in cancer.

Also, Dentelli et al[32] reported that STAT5A is a target of miR-222 in endothelial cells. MiR-222 controls inflammation-mediated neoangiogenesis by targeting STAT5A.