Long noncoding RNA CA7-4 promotes autophagy and apoptosis via sponging MIR877-3P and MIR5680 in high glucose-induced vascular endothelial cells
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Vascular endothelial cells (VECs) that form the inner wall of blood vessels can be injured by high glucose-induced autophagy and apoptosis. Although the role of long noncoding RNA in regulating cell fate has received widespread attention, long noncoding RNAs (lncRNAs) that can both regulate autophagy and apoptosis need to be discovered. In this study, we identified that a small chemical molecule, 3-benzyl-5-([2-nitrophenoxy] methyl)-dihydrofuran-2(3H)-one (3BDO), synthesized by us, could inhibit VEC autophagy and apoptosis induced by a high concentration of glucose. To find new lncRNAs that regulate autophagy and apoptosis in VECs, we performed lncRNA microarray analysis. We found and verified an upregulated lncRNA named CA7-4 that was induced by a high concentration of glucose could be downregulated by 3BDO most obviously among all of the detected lncRNAs. Meanwhile, we investigated the mechanism of CA7-4 in regulating VEC autophagy and apoptosis. The results showed that CA7-4 facilitated endothelial autophagy and apoptosis as a competing endogenous RNA (ceRNA) by decoying MIR877-3P and MIR5680. Further study elucidated that MIR877-3P could trigger the decrease of CTNNBIP1 (catenin beta interacting protein 1) by combining with its 3ʹ UTR and then upregulating CTNNB1 (catenin beta 1); MIR5680 inhibited the phosphorylation of AMP-activated protein kinase (AMPK) by targeting and decreasing DPP4 (dipeptidyl peptidase 4). Therefore, CA7-4, MIR877-3P and MIR5680 represent new signal pathways that regulate VEC autophagy and apoptosis under the high-glucose condition. Abbreviations: 3BDO: 3-benzyl-5-([2-nitrophenoxy] methyl)-dihydrofuran-2(3H)-one; 3ʹ UTR: 3ʹ untranslated region; AGO2: argonaute RISC catalytic component 2; AMPK: AMP-activated protein kinase/protein kinase AMP-activated; BAX/BCL2L4: BCL2 associated X, apoptosis regulator; BCL2: BCL2 apoptosis regulator; CASP3: caspase 3; ceRNA: competing endogenous RNA; CTNNB1: catenin beta 1; CTNNBIP1/ICAT: catenin beta interacting protein 1; DPP4: dipeptidyl peptidase 4; FGF2/FGF-2: fibroblast growth factor 2; HG: high concentration glucose (30 mM glucose); lncRNA: long noncoding RNA; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; miRNA: microRNA; MIR4778-3P: microRNA 4778-3p; MIR561-3P: microRNA 561-3p; MIR5680: microRNA 5680; MIR877-3P: microRNA 877-3p; MTOR: mechanistic target of rapamycin kinase; Mut: mutant; NC: negative control; NG: normal concentration glucose (5.5 mM glucose); PARP1: poly(ADP-ribose) polymerase 1; qPCR: quantitative real-time PCR; RNA-FISH: RNA-fluorescence in situ hybridization; ROS: reactive oxygen species; RT-PCR: reverse transcription polymerase chain reaction; siRNA: small interfering RNA; SQSTM1: sequestosome 1; TGFB2-OT1: TGFB2 overlapping transcript 1; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VECs: vascular endothelial cells; WT: wild typeInducer
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Hepatocellular carcinoma (HCC) as one of the most refractory cancers leads to high mortality worldwide. Long noncoding RNAs have been widely acknowledged as important biomarkers and therapeutic targets in HCC. In this study, we investigated the effects of long noncoding RNA FGFR3-AS1 on tumor growth and metastasis in HCC. First, we found that the expression of FGFR3-AS1 was upregulated about threefold in HCC samples and cell lines. We knocked down FGFR3-AS1 in Huh7 and Hep3B cells and found that FGFR3-AS1 knockdown significantly inhibited cell proliferation but induced apoptosis. Moreover, FGFR3-AS1 knockdown led to more HCC cells arrested in the G 0 stage. FGFR3-AS1 knockdown significantly inhibited cell migration and invasion. Additionally, we found that FGFR3-AS1 silencing dramatically delayed tumor growth in vivo. We found that, mechanistically, FGFR3-AS1 silencing decreased the activation of the PI3K/AKT signaling pathway. Taken together, our data demonstrated the pro-oncogenic role of FGFR3-AS1 in HCC and suggested that FGFR3-AS1 may serve as a novel biomarker for the diagnosis and therapeutic target for HCC treatment.
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Autophagy is a highly conserved cell degradation process which can decompose the organelles and recycling the macromolecules by lysosomes. Autophagy is induced by multiple factors, such as starvation, ischemia, and oxidative stress, and plays a key role in development and differentiation of cells. It has been shown that autophagy is closely related to cardiovascular diseases. Moderate autophagy protects myocardial cells from injury, whereas insufficient or excessive autophagy triggers or aggravates diseases. The present article reviews the progress of autophagy in cardiovascular diseases.
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Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Long noncoding RNAs (lncRNAs) are involved in the tumorigenesis and progression of some cancers. However, only a handful of lncRNAs have been functionally identified in HCC. In the present study, we identified a novel functional lncRNA in HCC, termed lncWDR26 (GenBank Accession no. RP11-365O16). Here, we reported that lncWDR26 was significantly downregulated in HCC tissues and cells. Moreover, decreased lncWDR26 expression correlates with larger tumor size, higher clinical stage, and tumor metastasis, and also predicts poor prognosis in patients with HCC. In HCC cells, overexpression of lncWDR26 inhibited growth and metastasis, both in vitro and in vivo. Mechanistically, lncWDR26 suppressed HCC growth and metastasis by inhibiting WDR26 transcription. Notably, lncWDR26 was associated with SIX homeobox 3 (SIX3), and this association was required for the repression of WDR26 transcription. Together, these results indicate that lncWDR26 is a tumor suppressor lncRNA that promotes tumor progression, leading us to propose that lncRNAs may serve as key regulatory hubs in HCC progression.
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