ABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) is usually diagnosed at late stages, making it the second cause of malignancy-related death across the world. Long noncoding RNAs (lncRNAs) are of significance to tumorigenesis, highly suggestive of their functional roles as novel biomarkers for cancer therapy. The current study investigated the specific role of lncRNA TPTE pseudogene 1 (TPTEP1) in HCC. METHODS: Expression of lncRNA TPTEP1, microRNA-454-3p (miR-454-3p) and discs large homolog 5 (DLG5) was determined in tissues samples from the recruited patients with HCC. Cell proliferation, migration and invasion assays were performed to determine effects of lncRNA TPTEP1, miR-454-3p and DLG5 on the malignant phenotype of tumor cells. Finally, the mouse HCC model was also established to disclose the tumor suppressor effects of lncRNA TPTEP1 in vivo. RESULTS: LncRNA TPTEP1 was downregulated both in HCC cells and tissues, and played a negative regulatory role in HCC cell proliferation, migration and invasion. Mechanistically, lncRNA TPTEP1 competitively bound to miR-454-3p, thereby upregulating its endogenous target DLG5. Moreover, lncRNA TPTEP1 hindered activation of the protein kinase B signaling pathway, causing inhibited malignant phenotypes of HCC cells. Also, lncRNA TPTEP1 suppressed tumor growth and extrahepatic metastasis (lung) via miR-454-3p/DLG5 axis. CONCLUSION: Taken together, this research revealed a concrete mechanism of lncRNA TPTEP1 in HCC.
Subject(s)
Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , Membrane Proteins/genetics , MicroRNAs/genetics , PTEN Phosphohydrolase/genetics , Tumor Suppressor Proteins/genetics , Animals , Biomarkers, Tumor/genetics , Carcinogenesis/genetics , Cell Movement/genetics , Cell Proliferation/genetics , Disease Models, Animal , Down-Regulation/genetics , Humans , Mice , Neoplasm Invasiveness/genetics , Proto-Oncogene Proteins c-akt/metabolism , Pseudogenes/genetics , RNA, Long Noncoding/genetics , Signal Transduction/genetics , Up-Regulation/geneticsABSTRACT
Atherosclerosis has been regarded as a major contributor to cardiovascular disease. The role of extracellular vesicles (EVs) in the treatment of atherosclerosis has been increasingly reported. In this study, we set out to investigate the effect of macrophages-derived EVs (M-EVs) containing miR-19b-3p in the progression of atherosclerosis, with the involvement of JAZF1. Following isolation of EVs from macrophages, the M-EVs were induced with ox-low density lipoprotein (LDL) (ox-LDL-M-EVs), and co-cultured with vascular smooth muscle cells (VSMCs). RT-qPCR and western blot assay were performed to determine the expression of miR-19b-3p and JAZF1 in M-EVs and in VSMCs. Lentiviral infection was used to overexpress or knock down miR-19b-3p. EdU staining and scratch test were conducted to examine VSMC proliferation and migration. Dual-luciferase gene reporter assay was performed to examine the relationship between miR-19b-3p and JAZF1. In order to explore the role of ox-LDL-M-EVs carrying miR-19b-3p in atherosclerotic lesions in vivo, a mouse model of atherosclerosis was established through high-fat diet induction. M-EVs were internalized by VSMCs. VSMC migration and proliferation were promoted by ox-LDL-M-EVs. miR-19b-3p displayed upregulation in ox-LDL-M-EVs. miR-19b-3p was transferred by M-EVs into VSMCs, thereby promoting VSMC migration and proliferation. mir-19b-3p targeted JAZF1 to decrease its expression in VSMCs. Atherosclerosis lesions were aggravated by ox-LDL-M-EVs carrying miR-19b-3p in ApoE-/- mice. Collectively, this study demonstrates that M-EVs containing miR-19b-3p accelerate migration and promotion of VSMCs through targeting JAZF1, which promotes the development of atherosclerosis.
Subject(s)
Atherosclerosis , Extracellular Vesicles , MicroRNAs , Animals , Atherosclerosis/metabolism , Cell Movement , Cell Proliferation , Co-Repressor Proteins/metabolism , Co-Repressor Proteins/pharmacology , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Extracellular Vesicles/metabolism , Lipoproteins, LDL/metabolism , Lipoproteins, LDL/pharmacology , Macrophages/metabolism , Mice , MicroRNAs/metabolism , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolismABSTRACT
LncRNA PITPNA-AS1 was a newly identified lncRNA which has never been studied in cancers. Whether PITPNA-AS1 participated in the development of hepatocellular carcinoma (HCC) is obscure. Given the coaction of lncRNAs and miRNAs to carcinogenesis, the purpose of the present research is to inquire how PITPNA-AS1 affects HCC progression. Firstly, PITPNA-AS1 was observed to be heightened in HCC tissues. Then function assays proved that overexpressing or silencing PITPNA-AS1 could manipulate the proliferation and motility of HCC cells. Besides, PITPNA-AS1 was located in the cytoplasm. Among the candidate miRNAs of PITPNA-AS1, miR-876-5p was an obvious target. Moreover, mechanism experiments validated that PITPNA-AS1 modulated WNT5A expression by targeting miR-876-5p. Rescue experiments affirmed that WNT5A silencing rescued the miR-876-5p suppression-induced cellular processes in PITPNA-AS1-silenced Hep3B cells. And in vivo experiments determined that PITPNA-AS1 regulated HCC progression in vivo via miR-876-5p/WNT5A pathway. In conclusion, this work shed lights on the modulatory mechanism of PITPNA-AS1/miR-876-5p/WNT5A axis in HCC, which might be pivotal for exploring effective diagnostic biomarkers and treatment strategies for HCC patients.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , MicroRNAs/genetics , Phospholipid Transfer Proteins/antagonists & inhibitors , RNA, Long Noncoding/genetics , Wnt-5a Protein/metabolism , Animals , Apoptosis , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Cell Movement , Cell Proliferation , Disease Progression , Female , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Neoplasm Invasiveness , Oligonucleotides, Antisense/genetics , Phospholipid Transfer Proteins/genetics , Prognosis , Survival Rate , Tumor Cells, Cultured , Wnt-5a Protein/genetics , Xenograft Model Antitumor AssaysABSTRACT
The prognostic value of programmed death-ligand 1 (PD-L1) in gastric cancer (GC) remains controversial. To clarify this problem, we performed a meta-analysis of research studies identified in the PubMed, EMBASE and the Cochrane Library databases. A total of 1,901 patients in 10 studies were enrolled in this meta-analysis, and the pooled hazard ratio (HR) of 1.64 (95% CI 1.11 to 2.43; P = 0.01) indicated that PD-L1 expression is associated with a shorter overall survival (OS). The pooled odds ratios (ORs) indicated that PD-L1 expression was associated with tumour size (OR = 1.87, 95% CI 1.25 to 2.78; P = 0.002) and lymph node status (OR = 2.17, 95% CI 1.04 to 4.52; P = 0.04). However, PD-L1 had no correlation with gender, age, cancer location, differentiation, depth of invasion, and tumour stage. This meta-analysis indicates that PD-L1 expression is a valuable predictor of the prognosis of patients with GC. PD-L1 expression could be used for identifying a subgroup of patients, who would potentially benefit from targeted therapy against PD-1 or PD-L1. Well-designed large-cohort studies are needed to confirm these findings.
