Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths among cancer patients. Genes correlated with the progression and prognosis of HCC are critically needed to be identified. In the present study, 3 Gene Expression Omnibus (GEO) datasets (GSE46408, GSE65372 and GSE84402) were used to analyze the differentially expressed genes (DEGs) between HCC and non-tumor liver tissues. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to clarify the functional roles of DEGs. A protein-protein interaction network was established to screen the hub genes associated with HCC. The prognostic values of hub genes in HCC patients were analyzed using The Cancer Genome Atlas (TCGA) database. The expression levels of hub genes were validated based on ONCOMINE, TCGA and Human Protein Atlas (HPA) databases. Notably, 56 upregulated and 33 downregulated DEGs were markedly enriched under various GO terms and four KEGG terms. Among these DEGs, 10 hub genes with high connectivity degree were identified, including cyclin B1, cyclin A2, cyclin B2, condensin complex subunit 3, PDZ binding kinase, nucleolar and spindle-associated protein 1, aurora kinase A, ZW10 interacting kinetochore protein, protein regulator of cytokinesis 1 and kinesin family member 4A. The upregulated expression levels of these hub genes in HCC tissues were further confirmed by ONCOMINE, TCGA, and HPA databases. Additionally, the increased mRNA expression of each hub gene was related to the unfavorable disease-free survival and overall survival of HCC patients. The present study identified ten genes associated with HCC, which may help to provide candidate targets for the diagnosis and treatment of HCC.
Our previous research suggests that 3-deoxyglucosone (3DG), formed in the caramelization course and Maillard reactions in food, is an independent factor for the development of prediabetes. Since the relationship between type 2 diabetes (T2D) and intestinal microbiota is moving from correlation to causality, we investigated the alterations in the composition and function of the intestinal microbiota in 3DG-induced prediabetic rats. Rats were given 50 mg/kg 3DG by intragastric administration for two weeks. Microbial profiling in faeces samples was determined through the 16S rRNA gene sequence. The glucagon-like peptide 2 (GLP-2) and lipopolysaccharide (LPS) levels in plasma and intestinal tissues were measured by ELISA and Limulus test, respectively. 3DG treatment did not significantly change the richness and evenness but affected the composition of intestinal microbiota. At the phylum level, 3DG treatment increased the abundance of nondominant bacteria Proteobacteria but did not cause the change of the dominant bacteria. Meanwhile, the abundance of the Prevotellaceae family and Parasutterela genus and the Alcaligencaeae family and Burkholderiales order and its attachment to the Betaproteobacteria class were overrepresented in the 3DG group. The bacteria of Candidatus Soleaferrea genus, Gelria genus, and Thermoanaerobacteraceae family and its attachment to Thermoanaerobacterales order were apparently more abundant in the control group. In addition, 45 KEGG pathways were altered after two-week intragastric administration of 3DG. Among these KEGG pathways, 13 KEGG pathways were involved in host metabolic function related to amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, and metabolism of terpenoids and polyketides. Moreover, the increased LPS levels and the decreased GLP-2 concentration in plasma and intestinal tissues were observed in 3DG-treated rats, together with the impaired fasting glucose and oral glucose tolerance. The alterations in composition and function of the intestinal microbiota were observed in 3DG-treated rats, which provides a possible mechanism linking exogenous 3DG intake to the development of prediabetes.
A recent study found an increased level of 3DG during oral glucose load in healthy individuals, which redirects our attention to the effect of high plasma 3DG level in the pathophysiology of type 2 diabetes mellitus. We found previously that abnormally elevated plasma 3DG was significantly associated with the impaired glucose regulation in non-diabetic seniors. The current study aimed to investigate the acute effects of exogenous 3DG on plasma 3DG levels, glucose tolerance and insulin levels. A significant increase in the plasma level of 3DG was observed in rats administrated 50 mg/kg 3DG i. v. even 2 h after. With the acute elevation of circulating 3DG, intravenous glucose tolerance of normal rats was impaired, whereas plasma insulin levels were higher. The 3DG-mediated impairment in glucose tolerance was associated with the attenuated insulin-stimulated glucose uptake in the adipose and liver tissues and the decreased glucose-stimulated insulin secretion in the pancreas tissue. In rats treated with 50 mg/kg 3DG i. v., a reduced phosphorylation of p85-PI3K was observed in both the liver and pancreas tissues. The increase in plasma levels of 3DG and the deleterious effects of 3DG were attenuated by aminoguanidine pretreatment. Our results indicated a close association of 3DG with diabetes through participating in inducing acute glucose intolerance involvement of PI3K signaling in healthy individuals. By such a mechanism, a 3DG-targeted intervention to attenuation of the acute elevation of circulating 3DG is promising new therapeutic and prevention strategies for diabetes and its complications.
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