Page 117 - Read Online

Almurshidi et al. Neuroimmunol Neuroinflammation 2019;6:11 I http://dx.doi.org/10.20517/2347-8659.2019.19 Page 7 of 11

Figure 3. FOXOs facilitate cell cycle and metabolic regulation, which ultimately regulates apoptosis. At the beginning stage of spinal cord
injury (SCI), FOXO1 activates the enzymes (e.g., superoxide dismutases or SODs) responsible for regulating oxidative stress from reactive
oxygen species (ROS). With time FOXO1 induces autophagy, controls inflammation, and leads to cell cycle arrest. The role of miR-96 is
most profound during the secondary stage of SCI, whereby it regulates FOXO proteins, including FOXO1 to enhances the survival of cells.
FOXO3a is also down regulated by miR-96 affecting the expression of inflammatory pathways during SCI. This process also affects pro-
apoptotic factors such as TRAIL, Fas, and Puma

FOXO subfamily, specifically FOXO3a and FOXO1. Inhibiting miR-96 upregulates FOXO1 and FOXO3a
[68]
expression, suppressing colony formation and cell proliferation in HCC .

Studies have also shown that prostate cancer is associated with elevated expression of miR-96 and
[69]
subsequent down regulation of FOXO1, a phenomenon that can be leveraged to control cell proliferation .
Other investigators studied the same phenomenon with a dataset containing non-malignant benign
[70]
prostate tissue samples and prostate cancer tissue samples . According to these researchers,
overexpression of miR-96 decreases FOXO1 expression in both the non-malignant tissue samples and the
prostate cancer tissue samples, even when the two samples are combined. Down regulation of FOXO3a
[71]
and p27kip1 promotes axonal regeneration and proliferation of glial cells after SCI in rats . An earlier
investigation showed that down regulation of FOXO3a decreased p27kip1 at mRNA and protein levels after
[72]
injury . A recent study shows that miR-96 is highly essential for normal development of the auditory
[73]
system, which is required for functional maturation in the peripheral and central auditory system .
miR-96 in regulation of FOXO pathway and other molecular pathways
FOXO pathways are of vital importance in regulating biological processes such as glucose metabolism,
[74]
cellular proliferation, apoptosis, and repair of DNA damage . FOXO transcription factors are also crucial
in controlling neurodegenerative disorders through autophagy and apoptosis in the presence of oxidative
[75]
stress . Mounting evidence demonstrates that miR-96 plays a crucial role in regulating these FOXO
pathways. For example, the expression of FOXO3a and FOXO1 is suppressed by miR-96, which controls the
[76]
cell cycle, cell proliferation, and migration . FOXO3a transcriptionally down regulates the level of p27kip1
(an important neurogenesis regulatory factor in mammals) positioning it as a candidate for controlling axonal
[77]
regeneration after SCI. The role of miR-96 in regulating FOXO pathways has also been studied in vitro ,
demonstrating that miR-96 binds to the FOXO1 3’UTR sequence lowering the transcript levels of FOXO1
and elevating cell growth [Figure 3].