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2015 ; 11
(12
): 2172-83
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A new microRNA signal pathway regulated by long noncoding RNA TGFB2-OT1 in
autophagy and inflammation of vascular endothelial cells
#MMPMID26565952
Huang S
; Lu W
; Ge D
; Meng N
; Li Y
; Su L
; Zhang S
; Zhang Y
; Zhao B
; Miao J
Autophagy
2015[]; 11
(12
): 2172-83
PMID26565952
show ga
TGFB2-OT1 (TGFB2 overlapping transcript 1) is a newly discovered long noncoding
RNA (lncRNA) derived from the 3'UTR of TGFB2. It can regulate autophagy in
vascular endothelial cells (VECs). However, the mechanisms of TGFB2-OT1 action
are unclear, and whether it is involved in VECs dysfunction needs investigation.
Here, the level of TGFB2-OT1 was markedly increased by lipopolysaccharide and
oxidized low-density lipoprotein, 2 VECs inflammation triggers. A chemical small
molecule, 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO)
significantly decreased TGFB2-OT1 levels and inhibited the effect of LPS and
oxLDL. The NUPR1 level was upregulated by the 2 inflammation inducers and
modulated the TGFB2-OT1 level by promoting the expression of TIA1, responsible
for TGFB2-OT1 processing. We focused on how TGFB2-OT1 regulated autophagy and
inflammation. Use of miRNA chip assay, TGFB2-OT1 overexpression technology and
3BDO revealed that TGFB2-OT1 regulated the levels of 3 microRNAs, MIR3960,
MIR4488 and MIR4459. Further studies confirmed that TGFB2-OT1 acted as a
competing endogenous RNA, bound to MIR3960, MIR4488 and MIR4459, then regulated
the expression of the miRNA targets CERS1 (ceramide synthase 1), NAT8L
(N-acetyltransferase 8-like [GCN5-related, putative]), and LARP1 (La
ribonucleoprotein domain family, member 1). CERS1 and NAT8L participate in
autophagy by affecting mitochondrial function. TGFB2-OT1 increased the LARP1
level, which promoted SQSTM1 (sequestosome 1) expression, NFKB RELA and CASP1
activation, and then production of IL6, IL8 and IL1B in VECs. Thus, NUPR1 and
TIA1 may control the level of TGFB2-OT1, and TGFB2-OT1 bound to MIR3960, MIR4488
and MIR4459, which targeted CERS1, NAT8L, and LARP1, respectively, the key
proteins involved in autophagy and inflammation.