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Transcriptome Analysis of Liver cancer cell Huh-7 Treated with Metformin

ABSTRACT: Metformin is a kind of widely used antidiabetic agent, which regulates glucose homeostasis through inhibiting liver glucose production and increasing glucose uptake in muscle. Recent studies suggest that metformin exhibits anticancer properties in a variety of cancers. Although several antitumor mechanisms have been proposed for metformin action, its mode of action in human liver cancer remains not elucidated. In our study we investigated the underlying molecular mechanisms of metformin’s antitumor effect on Huh-7 cells of hepatocellular carcinoma (HCC) in vitro. RNA sequencing (RNA-seq) was performed to explore the effect of metformin on the transcriptome of Huh-7 cells. The results revealed that 4518 genes (with log2 fold change>1 or < -1, p-adjusted value<0.05) were differentially expressed in Huh-7 cells with treatment of 25mM metformin compared to 0mM metformin including 1812 up-regulated and 2706 down-regulated genes. Gene ontology and KEGG pathway analyses identified 54 classical pathways which were significantly enriched, and 16 pathways are closely associated with cancer, such as cell cycle, DNA replication, ECM-receptor interaction and so on. We selected 11 differentially expressed genes, which are closely associated with HCC to validate their differential expressions through quantitative real-time reverse transcription PCR (qRT-PCR). The result exhibited that the genes of FASN, MCM6, MCM5, MARCKS, FADS2, CXCL1, BMP4, SKP2, KNG1, PCNA were down-regulated and DUSP1 is significantly up-regulated in Huh-7 cells with treatment of 25mM metformin. These differentially expressed genes and pathways might play a crucial part in the antitumor effect of metformin, and might be potential targets of metformin treating HCC. Further investigations are required to evaluate the metformin mechanisms of anti-cancer action in vivo.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190076 | GEO | 2021/12/05

REPOSITORIES: GEO

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Project description:Obesity-induced insulin resistance of the liver is characterised by increased gluconeogenesis, which contributes to elevated blood glucose levels in individuals with type 2 diabetes. Research into how fatty acids induce insulin resistance has commonly focused on the induction of insulin resistance. We hypothesise that by shifting focus to the reversal of an insulin resistant phenotype, novel insights can be made into the mechanisms by which insulin resistance can be overcome. Using global gene and lipid expression profiling, we aimed to identify biological pathways altered in parallel with restoration of palmitate-induced deregulation of glucose production using metformin and sodium salicylate. FAO hepatoma cells were treated with palmitate (0.075mM, 48h) with or without metformin (0.25mM) and sodium salicylate (2mM) in the final 24h of palmitate treatment, and effects on glucose production were determined. Microarray followed by gene set enrichment analysis was performed to investigate pathway regulation. A lipidomic analysis (HPLC-MS/MS) and measurement of secreted bile acids and cholesterol were performed. Reversal of palmitate-induced impairment of glucose production by metformin and sodium salicylate was characterised by down-regulated expression of metabolic pathways regulating acetyl-CoA to cholesterol and bile acid biosynthesis. Total levels of intracellular and secreted cholesterol and bile acids were not different between impaired and restored glucose production. Total intracellular levels of diacylgycerol, triacylglycerol and cholesterol esters increased with palmitate (impaired glucose production), however, these were not further altered with metformin and sodium salicylate (restored glucose production). Six individual lipid species containing 18:0 and 18:1 side-chains were reduced by metformin and sodium salicylate. Widespread lipid metabolism changes induced by the reversal of palmitate-induced deregulation of glucose production with metformin and sodium salicylate were identified. While cholesterol and bile acid levels remained unchanged, the flux through these pathways may in part explain these findings. The identification of lipid species containing 18:0 and 18:1 side chains being regulated alongside changes to glucose production may indicate potential mediators of glucose production and insulin resistance. Three-condition experiment, Vehicle, Palmitate (PA) and Palmitate (PA) + Metformin (Met) + Sodium Sailcylate (NaS) with biological replicates: 8 Vehicle, 20 PA and 20 PA+Met+NaS , independently grown and harvested. One replicate per array.

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Transcriptome Analysis of Liver cancer cell Huh-7 Treated with Metformin

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