Abstract
MicroRNA (miR)-210 is the most consistently and predominantly up-regulated miR in response to hypoxia in multiple cancer cells. The roles of miR-210 in rat adrenal gland pheochromocytoma (PC-12) cells remain unknown. We aimed to explore the possible effect of miR-210 in neonatal brain injury. We explored the potential molecular mechanism by using PC-12 cells under hypoxia. Scramble miRs, miR-210 mimic, miR-210 inhibitor or its negative control were respectively transfected into PC-12 cells. Cell viability, migration, invasion and apoptosis were also assessed to evaluate hypoxia-induced cell injury. The expression level of miR-210 was identified by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Apoptosis-related protein expression as well as key kinases in the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signal pathway was studied by Western blot analysis. Hypoxia suppressed cell viability, migration and invasion, but promoted apoptosis through activation of mitochondrial- and caspase-dependent pathways. Hypoxia markedly induced up-regulation of miR-210 in PC-12 cells. Overexpression of miR-210 protected PC-12 cells against hypoxia-induced injury. Bcl-2 adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) was proven to be a target gene of miR-210 in PC-12 cells. miR-210 overexpression ameliorated the hypoxia-induced injury in PC-12 cells by down-regulating BNIP3. Hypoxia-induced alterations of key kinases in the PI3K/AKT/mTOR signal pathway were affected by aberrant expression of BNIP3. These findings suggested that miR-210 protected PC-12 cells against hypoxia-induced injury by targeting BNIP3, involving the PI3K/AKT/mTOR signal pathway.
Highlights
Neonatal brain injury is a type of non-progressive brain damage; there are several contributing factors including congenital cerebral dysgenesis, cerebral palsy, infantile severe illness and nervous system dysfunction caused by trauma
We aimed to investigate the possible roles of miR-210 in neonatal brain injury using an in vitro cell model with hypoxia injury, and to explore the potential molecular mechanism, involving Bcl-2 adenovirus E1B kDa-interacting protein 3 (BNIP3) and the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways, in PC-12 cells
MiR-210 in Hypoxia-Treated PC-12 Cells the hypoxia-induced decreases were further decreased by BNIP3 overexpression (P < 0.01), but were reversed by BNIP3 knockdown (P < 0.001). These results suggested that hypoxia-induced inhibition of the PI3K/AKT/mTOR signal pathway was further inhibited by BNIP3 overexpression
Summary
Neonatal brain injury is a type of non-progressive brain damage; there are several contributing factors including congenital cerebral dysgenesis, cerebral palsy, infantile severe illness and nervous system dysfunction caused by trauma (du Plessis and Volpe, 2002; Hagberg, 2004; Ma and Zhang, 2017). As the term ‘‘neonatal brain injury’’ suggests, it mainly occurs in the perinatal period and preterm infants (Ma and Zhang, 2017). This injury is associated with severe morbidity and mortality rates where 50% of newborns die or have permanent neurological deficits (Fotopoulos et al, 2001). Moderate to severe neonatal brain injury occurs at a rate of 0.1%–0.2% of full-term live births, along with a total incidence of 0.3%–0.5% (Whitelaw and Thoresen, 2002; Shankaran and Laptook, 2007; Gonzalez and Ferriero, 2008). For better understanding of the disease pathogenesis and for better management of neonatal brain injury, elucidation of the underlying molecular mechanism will be of great significance
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