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A retrospective study of NENs and miR-224 promotes apoptosis of BON-1 cells by targeting PCSK9 inhibition.

ABSTRACT: Neuroendocrine neoplasms (NENs) represent relatively rare tumors. The lack of diagnostic, therapeutic method and prognostic factors makes them a challenge to us. We retrospectively reviewed the data of 205 NENs patients among which 157 cases were followed-up. Proprotein convertase subtilisin/kexin 9 (PCSK9), a regulator of low density lipoprotein cholesterol (LDL-C), was confirmed as a target gene of microRNA-224. We found an increased incidence of NENs from 2012 to 2015. Women were usually diagnosed at earlier stages than men (P < 0.05). Tumor grading was associated with primary tumor site, especially esophagus and cardia NENs all at G3 (P <0.001). Age, tumor grading and LDL-C levels were independent risk factors of digestive NENs. Low LDL-C level was significantly correlated with survival rate and median overall survival (OS, P < 0.05). MicroRNA-224 agomir and PCSK9 siRNA could promote apoptosis and suppress proliferation, invasion of BON-1 cells (P < 0.05), but increase the level of glucocorticoid (GC, P < 0.05). Taken together, age, tumor grading and LDL-C level are independent risk factors of NENs. The miR-224/PCSK9/GC axis binds to tumorigenesis and prognosis of pancreatic NENs (p-NENs).

SUBMITTER: Bai J

PROVIDER: S-EPMC5351680 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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A retrospective study of NENs and miR-224 promotes apoptosis of BON-1 cells by targeting PCSK9 inhibition.

Bai Jian'an J Na He H Hua Xiumei X Wei Yaling Y Ye Tian T Zhang Yiqiang Y Jian Guo G Zeng Weiwen W Yan Lijun L Tang Qiyun Q

Oncotarget 20170101 4

Neuroendocrine neoplasms (NENs) represent relatively rare tumors. The lack of diagnostic, therapeutic method and prognostic factors makes them a challenge to us. We retrospectively reviewed the data of 205 NENs patients among which 157 cases were followed-up. Proprotein convertase subtilisin/kexin 9 (PCSK9), a regulator of low density lipoprotein cholesterol (LDL-C), was confirmed as a target gene of microRNA-224. We found an increased incidence of NENs from 2012 to 2015. Women were usually diag ...[more]

PMID: 28036293

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Project description:Background Endothelial dysfunction and deregulated microRNAs (miRNAs) participate in the development of sepsis and are associated with septic organ failure and death. Here, we explored the role of miR-15b-5p on inflammatory pathways in lipopolysaccharide (LPS)-treated human endothelial cells, HUVEC and TeloHAEC. Methods The miR-15b-5p levels were evaluated in LPS-stimulated HUVEC and TeloHAEC cells by quantitative real-time PCR (qRT–PCR). Functional experiments using cell counting kit-8 (CCK-8), transfection with antagomir, and enzyme-linked immunosorbent assays (ELISA) were conducted, along with investigation of pyroptosis, apoptosis, autophagy, and mitochondrial reactive oxygen species (ROS) by cytofluorometric analysis and verified by fluorescence microscopy. Sirtuin 4 (SIRT4) levels were detected by ELISA and immunoblotting, while proprotein convertase subtilisin-kexin type 9 (PCSK9) expression was determined by flow cytometry (FACS) and immunofluorescence analyses. Dual-luciferase reporter evaluation was performed to confirm the miR-15b-5p–SIRT4 interaction. Results The results showed a correlation among miR-15b-5p, PCSK9, and SIRT4 levels in septic HUVEC and TeloHAEC. Inhibition of miR-15b-5p upregulated SIRT4 content, alleviated sepsis-related inflammatory pathways, attenuated mitochondrial stress, and prevented apoptosis, pyroptosis, and autophagic mechanisms. Finally, a PCSK9 inhibitor (i-PCSK9) was used to analyze the involvement of PCSK9 in septic endothelial injury. i-PCSK9 treatment increased SIRT4 protein levels, opposed the septic inflammatory cascade leading to pyroptosis and autophagy, and strengthened the protective role of miR-15b-5p inhibition. Increased luciferase signal validated the miR-15b-5p–SIRT4 binding. Conclusions Our in vitro findings suggested the miR-15b-5p–SIRT4 axis as a suitable target for LPS-induced inflammatory pathways occurring in sepsis, and provide additional knowledge on the beneficial effect of i-PCSK9 in preventing vascular damage by targeting SIRT4. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s11658-023-00482-5.

Project description:A microarray analysis of an animal model with experimental sepsis induced by caecal ligation and puncture revealed that the level of microRNA?195 (miR?195) was upregulated. However, to the best of our knowledge, the role of miR?195 in sepsis remains unknown. The present study investigated the effect of miR?195 on apoptosis in sepsis and investigated the underlying mechanism. The level of miR?195 was measured in human intestinal epithelial cells following exposure to lipopolysaccharide (LPS). Cell viability and apoptosis were detected using Cell Counting kit?8 and flow cytometry assays. The expression levels of apoptosis?associated proteins were determined using western blot analysis. In addition, a dual?luciferase reporter assay was employed to verify the association between miR?195 and sirtuin 1 (SIRT1). Furthermore, the SIRT1 inhibitor EX527 was applied to further confirm the regulatory network of miR?195/SIRT1 in LPS?induced apoptosis. It was demonstrated that LPS significantly inhibited cell viability and promoted cell apoptosis in NCM460 cells in a dose?dependent manner. In addition, miR?195 was significantly upregulated following LPS treatment. The present results revealed that silencing miR?195 prevented apoptosis and alleviated cell injury in LPS?induced NCM460 cells. Further investigation demonstrated that miR?195 bound directly to and negatively regulated SIRT1. Inhibition of SIRT1 reversed the protective effects of miR?195?silencing on the apoptosis and viability of NCM460 cells. Furthermore, silencing miR?195 prevented endoplasmic reticulum (ER) stress?induced apoptosis via a downregulation of SIRT1 and its downstream effectors, including activating transcription factor 4, C/EBP homologous protein, glucose?regulated protein 78 and growth arrest and DNA?damage protein 34, as well as the phosphorylation of eukaryotic translation initiation factor 2A. In conclusion, the present study revealed a novel mechanism by which miR?195 regulates SIRT1?mediated downstream effectors in ER stress?induced apoptosis in sepsis.

Dataset Information

A retrospective study of NENs and miR-224 promotes apoptosis of BON-1 cells by targeting PCSK9 inhibition.

Publications

A retrospective study of NENs and miR-224 promotes apoptosis of BON-1 cells by targeting PCSK9 inhibition.

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