The occurrence and the subsequent development of pulmonary arterial hypertension (PAH) involve complicated mechanisms. Of these, the proliferation of pulmonary artery smooth muscle cells (PASMCs) has been indicated to be closely associated with its progression. Therefore, therapeutic methods targeting PASMCs to inhibit proliferation is an effective method for alleviating PAH. The present study was designed to determine the role of the adenosine A(2A) receptor (A2A receptor) in hypoxia‑induced rat PASMC (RPASMC) proliferation. Primary RPASMCs were isolated from the pulmonary artery of adult male SD rats, cultured and used for the following experiments. The mRNA level and protein expression of CXCR4 were measured by reverse transcription‑quantitative polymerase chain reaction and western blot analysis, respectively. The cell proliferation of RPASMCs was measured using a cell proliferation assay kit. In the present study, it was demonstrated that the proliferation of RPASMCs was partially mediated by activation of the stromal cell‑derived factor 1 (SDF1)‑CXC chemokine receptor 4 (CXCR4) axis under hypoxic conditions. In addition, SDF1‑α alone upregulated the mRNA and protein expression levels of CXCR4, and stimulated the proliferation of RPASMCs. The protein expression of CXCR4 and the cell proliferation were markedly inhibited by application of A2A receptor agonist CGS21680 or cyclic adenosine monophosphate (cAMP) under hypoxic conditions or treatment with SDF1‑α and was reversed by the A2A receptor antagonist SCH58261 or 8‑bromoadenosine‑3',5'‑cyclic monophosphorothioate. These results demonstrated that the inhibition of SDF1‑CXC4 signaling by the activation of A2A receptor and subsequent increase in the level of cAMP may be a potential method to ameliorate PAH.
Recent years have seen a rapid increase in the incidence of nonalcoholic steatohepatitis (NASH)-derived liver cancer, the heterogeneity-specific nature of biomarkers is significantly contributing to the high mortality rate worldwide.
Objective: To screen new pathogenic genes associated with nonalcoholic steatohepatitis-derived hepatocellular carcinoma (NASH-related HCC) and related pathways, and break through the heterogeneity barrier.
Methods: Differentially expressed genes (DEGs) were screened using a gene expression chip. Gene Ontology (GO) and KEGG analyses were performed after. We then built protein-protein interaction (PPI) networks to identify hub gene. The diagnostic and prognostic role of the hub genes in NASH-related HCC patients of various clinicopathological features were revealed by a comprehensive bioinformatics approach.
Results: The following 10 HUB genes were identified: YWHAZ, JUN, MDM2, ACTR3, HNRNPA2B1, FOS, CANX, RBBP4, RBFOX3, and RAC1. These genes were mainly enriched in pathways such as cell division, cell metabolism, protein binding. We further revealed that all the hub genes were significantly dysregulated in HCC patients of various clinicopathological features including different races, cancer stages, genders, age groups, and body weights. Additionally, some chemotherapeutic drugs were found to interact with hub gene.
Conclusions: The genes identified in this study might play a crucial role in the progression of NASH to hepatocellular carcinoma and as potential biomarkers of NASH-HCC patients that could help to overcome the heterogenetic-specific barrier across different clinicopathological features.
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