title: A new microRNA signal pathway regulated by long noncoding RNA TGFB2-OT1 in autophagy and inflammation of vascular endothelial cells.
abstract: 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.
authors.affiliation: a Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University ; Jinan , China.
authors.forename: ShuYa
authors.initials: S
authors.lastname: Huang
authors.affiliation: a Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University ; Jinan , China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: a Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University ; Jinan , China.
authors.forename: Di
authors.initials: D
authors.lastname: Ge
authors.affiliation: b Institute of Organic Chemistry; School of Chemistry and Chemical Engineering; Shandong University ; Jinan , China.
authors.forename: Ning
authors.initials: N
authors.lastname: Meng
authors.affiliation: a Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University ; Jinan , China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: a Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University ; Jinan , China.
authors.forename: Le
authors.initials: L
authors.lastname: Su
authors.affiliation: a Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University ; Jinan , China.
authors.forename: ShangLi
authors.initials: S
authors.lastname: Zhang
authors.affiliation: c The Key Laboratory of Cardiovascular Remodeling and Function Research; Chinese Ministry of Education and Chinese Ministry of Health; Qilu Hospital; Shandong University ; Jinan , China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: b Institute of Organic Chemistry; School of Chemistry and Chemical Engineering; Shandong University ; Jinan , China.
authors.forename: BaoXiang
authors.initials: B
authors.lastname: Zhao
authors.affiliation: a Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University ; Jinan , China.|c The Key Laboratory of Cardiovascular Remodeling and Function Research; Chinese Ministry of Education and Chinese Ministry of Health; Qilu Hospital; Shandong University ; Jinan , China.
authors.forename: JunYing
authors.initials: J
authors.lastname: Miao
mesh_terms: D001343:Autophagy / Q000235:genetics*; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D053781:Transforming Growth Factor beta2 / Q000235:genetics*
chemical_list: D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D035683:MicroRNAs; D062085:RNA, Long Noncoding; C509041:TGFB2 protein, human; D053781:Transforming Growth Factor beta2; C000611845:long noncoding RNA TGFB2-OT1, human; C099252:oxidized low density lipoprotein
keywords: 3′UTR-derived RNA; autophagy; ceRNA; inflammation; lncRNA; microRNA