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inhibitor, which was involved in the regulation of several cellular processes such as differentiation,
[31]
[31]
survival, motility and cell cycle . MiR-126 affected EPC function via its target SPRED1 . PI3K/AKT/
eNOS pathway played a role in preventing high glucose-induced cell injury . As mentioned above,
[31]
[5]
miR-126 activated PI3K/AKT/eNOS signal pathway and rescued EPC function by degrading PIK3R .
MiR-126 expression was down-regulated in type II diabetic derived EPCs. MiR-126 overexpression in
[31]
EPCs promoted EPC proliferation, migration, and inhibited EPC apoptosis . Experiments demonstrated
that endothelial micro-particles derived from glucose-treated ECs had lower amounts of miR-126, which
[32]
reduced endothelial repair capacity in vitro and in vivo . It could speculate that miR-126 up-regulation in
glucose-damaged ECs protected them from glucose-induced dysfunction.

[33]
In consistent with above reports, Zampetaki et al. demonstrated that loss of miR-126 was associated
with diabetics. MiR-126 level in endothelial apoptotic bodies was reduced in a glucose-dependent fashion.
Low plasma miR-126 level caused VEGF resistance and endothelial dysfunction, which related to diabetics
[33]
complications .

MiR-126 activated VEGF signaling by repressing SPRED1 and PI3R2. Circulating miR-126 has been
proposed as a marker for endothelial dysfunction in diabetics. Therefore, up-regulating miR-126 in plasma
provided a unique approach for the therapy of endothelial injury.

MIR-126 AND TUMOR
There was no doubt that miR-126 was related to tumorigenic process. Studies showed that MiR-126 was not
only a tumor suppressor, but also an oncogene depending on the type of cancer [34-39] . MiR-126 negatively
cancer cell proliferation, migration, invasion and survival while it also accelerated cancer progression
[34]
through the promotion of microvessel formation .

Increase of miR-126 was beneficial for the acute myelocytic leukemia (AML) through degrading HOXA9.
[35]
HOXA9 was an oncogene and often elevated in myelocytic leukemia . However, miR-126 overexpression
[36]
in AML was associated with poor survival and higher chance of relapse . Decrease of miR-126 expression
in AML cells reduced cell growth by inducing apoptosis in vitro .
[36]
Transferring miR-126 mimics into colon cancer cells reduced cell viability, migration, and invasion by
[40]
degrading CXCR4 . SDF-1 binding to CXCR4 activated NF-kB pathway and increased MMP-2, MMP-9,
VEGF and nitric oxide expression. These factors promoted tumor cell invasion through degradation of the
[41]
extracellular matrix and promotion of angiogenesis, hematopoiesis, ECs growth .

MiR-126 is an inhibiting microRNA on the tumor development [38,39] . Studies demonstrated that VEGF-A
was a target of MiR-126, which could down-regulate miR-126 and increase VEGF-A expression in
[38]
tumors . In malignant mesothelioma, miR-126 indirectly increased FOXO1 by targeting IRS1 leading to
[39]
apoptosis, cell cycle arrest, and stress resistance in various tissues .
According to current researches, miR-126 was down-regulated in most tumors such as colorectal cancer,
gastric cancer, lung cancer, breast cancer. However, miR-126 was up-regulated in the acute myeloid
[36]
[42]
leukemia . MiR-126 could be a tumor marker in a non-invasive diagnostic method .
In conclusion, miR-126 is a double-edged sword and plays distinct roles in different cell types and
microenvironment. It could be a potential therapeutic target and prognostic biomarker for the vascular
disease, diabetics and tumor. Exploring the effects and underlying mechanisms of miR-126 is important
and timely.