RESUMO
Abnormal function of endothelial cells (ECs) is an important reason for vascular endothelial remodeling and atherosclerotic plaque formation in patients with atherosclerosis (AS). Here, we report for the first time that the vascular ECs with apoptosis resistance phenotype (ARECs) exist in peripheral blood of AS patients. Our research data showed that the switch of regulation modes between HIF-1α and Bax operated by lncRNA-ASLNC18810 is the direct cause for the formation of ARECs. When ASLNC18810 is low or missing, HIF-1α indirectly negatively regulates the Bax in post-transcription through HIF-1α/miR-559/Bax pathway which makes ECs acquire apoptosis resistance and form ARECs. The functional experiments results showed that ASLNC18810 could effectively eliminate the anti-apoptotic properties of ARECs by blocking the HIF-1α/miR559/Bax pathway and maintaining HIF-1α/Bax pathway. In a word, our study shows that ASLNC18810 has full potential to become a biological target for the prevention and treatment of atherosclerotic plaques by regulating ARECs. ASLNC18810 was significantly upregulated in ECs compared to ARECs. With high level of ASLNC18810 in ECs, ASLNC18810 binds to miR-559 as a miRNA sponge and suppresses the inhibition effect of miR-559 on Bax protein, this direct positive transcriptional regulation between HIF-1α and Bax endows the apoptotic property in ECs induced by Ox-LDL. However, with low expression of ASLNC18810 in ARECs, the post-transcriptional regulation of Bax by miR-559 dominates and the indirect negative regulation between HIF-1α and Bax endows the anti-apoptotic property of ARECs. To sum up, low ASLNC18810 expression-mediated switching of HIF-1α/Bax pathway to HIF-1α/miR-559/Bax pathway is the internal reason for ECs to obtain apoptosis resistance and the formation of ARECs under the ox-LDL induction.
Assuntos
Aterosclerose , MicroRNAs , Placa Aterosclerótica , RNA Longo não Codificante , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Células Endoteliais/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Apoptose , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/farmacologiaRESUMO
Cyclin B1 (CCNB1) is regarded as an oncogene in multiple tumors. This work aims to investigate the expression, function, and related mechanisms of CCNB1 in ovarian carcinoma (OC). Three microarray datasets (GSE14407, GSE18520, and GSE54388) were obtained from the Gene Expression Omnibus (GEO) database and screened for differentially expressed genes (DEGs) of OC tissues and normal ovarian tissues. CCNB1 expression in OC tissues and paracancerous tissues was detected by immunohistochemistry. Kaplan-Meier plotter database was utilized to analyze the correlation between CCNB1 expression and the prognosis of OC patients. After the loss-of-function and gain-of-function cell models were established, cell counting kit-8 (CCK-8), bromo-deoxyuridine (BrdU), and transwell experiments were employed to examine the proliferation, migration, and invasion of OC cells, respectively. The targeting relationship between miR-559 and CCNB1 was verified using the dual-luciferase reporter gene experiment. The expressions of CCNB1 mRNA and miR-559 were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Western blot was used to quantify the protein expression of CCNB1. In addition, xenograft nude mouse models were established to examine the effects of CCNB1 on lung metastasis in vivo. CCNB1 expression was markedly increased in OC tissues and cell lines. The overall survival, progression-free survival, and post-progression survival of OC patients with high CCNB1 expression were significantly shorter. OC cell proliferation, migration, and invasion were enhanced by CCNB1 overexpression while CCNB1 knockdown led to opposite effects. MiR-559 expression was remarkably reduced in OC tissues and cell lines, and miR-559 markedly suppressed the malignant characteristics of OC cells. Besides, miR-559 directly targeted the 3' UTR of CCNB1 mRNA and reduced CCNB1 expression at both the mRNA and protein levels. Overexpression of CCNB1 accelerated lung metastasis of OC cells in vivo. CCNB1, of which expression is modulated by miR-559, facilitates proliferation, migration, and invasion of OC cells, therefore, working as a potential therapeutic target of OC. This work provides new insights into the clinical diagnosis and treatment of OC.
Assuntos
Neoplasias Pulmonares , MicroRNAs , Neoplasias Ovarianas , Regiões 3' não Traduzidas , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Ciclina B1/genética , Ciclina B1/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologiaRESUMO
Hepatocellular carcinoma (HCC) is one of the common malignant tumors with poor overall prognosis. As a tumor suppressor, the function of miR-559 in HCC is not clear. In this study, quantitative real-time PCR was carried out to measure the expression of miR-559 in HCC cell lines. The effects of miR-559 on HCC cell proliferation, migration, and invasion were evaluated through a series of functional assays. The mechanism through which miR-559 regulates HCC cells was investigated by dual-luciferase reporter assay and functional experiments. The results revealed that miR-559 expression was low in HCC cell lines. Upregulation of miR-559 suppressed HCC cell proliferation, migration, and invasion. Dual-luciferase reporter assay confirmed Golgi membrane protein 73 (GP73) as a target gene of miR-559. Moreover, miR-559 could negatively regulate GP73 expression in HCC cells. These results demonstrated that low-level expression of miR-559 was associated with HCC, and overexpression of miR-559 could inhibit HCC cell growth and invasion via targeting GP73.
Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Proteínas de Membrana/genética , MicroRNAs/genéticaRESUMO
Background: MicroRNAs (miRNAs) participate in gene regulation and the control of cancer-related mechanisms such as apoptosis, invasion and differentiation. Single nucleotide polymorphisms (SNP) of the miRNA encoding genes may influence the development of cancer. We hypothesized a link between miR-559 SNP rs58450758 and breast cancer.Materials & methods: Bioinformatics analyses were performed to predict the miR-559 target genes and the effect of the rs58450758 SNP on the stem-loop structure. A total of 129 breast cancer cases and 153 controls were genotyped using PCR-RFLP.Results: The recessive genotype (TT) was more common among breast cancer patients (23.3%) than among controls (2%). The non-dominant genotypes (CT+TT) were associated with breast cancer in patients (OR 3.62; 95% CI, 1.95-6.69; p < 0.0001). Bioinformatics analyses suggested that rs58450758 changes miR-559 secondary structure and forms new DICER sites in the pre-miRNA.Conclusion: The miR-559 rs58450758 variant is linked to breast cancer.