ABSTRACT
Pancreatic cancer (PC) is one of the most malign human cancers, with its underlying molecular mechanisms largely unknown. In this work, we investigated the mechanistic role of protein arginine methyltransferase 1 (PRMT1) gene in PC. Expression of PRMT1 in immortal PC cell lines and clinical human PC tumors was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. In PANC-1 and SW1990 cells, PRMT1 was either downregulated by lentiviral-mediated short hairpin RNA (shRNA) or upregulated by overexpression plasmid. The effects of PRMT1 downregulation or upregulation on PC proliferation and invasion in vitro, and xenograft in vivo, were evaluated. Gene expression of PRMT1 downstream target, zinc finger E-box binding homeobox 1 (ZEB1) was measured in PRMT1-downregulated PC cells. ZEB1 was also upregulated in PRMT1-downregulated PC cells to evaluate its functional role in PRMT1-mediated regulation in PC. PRMT1 was downregulated in both PC cell lines and human tumors. PRMT1 downregulation in PANC-1 and SW1990 cells significantly suppressed cancer proliferation and invasion in vitro and xenograft in vivo. However, PRMT1 overexpression did not have function impact in PC cells. ZEB1 gene expression was suppressed in PRMT1-downregulated PC cells. Subsequently, overexpressing ZEB1 reversed the antitumor effects of PRMT1 downregulation in PC cells. PRMT1 was aberrantly upregulated in PC. PRMT1 inhibition, possibly inversely acting through ZEB1, might be an effective molecular intervention to inhibit PC growth and invasion. © 2018 IUBMB Life, 70(10):1032-1039, 2018.
Subject(s)
Cell Proliferation/genetics , Pancreatic Neoplasms/genetics , Protein-Arginine N-Methyltransferases/genetics , Repressor Proteins/genetics , Zinc Finger E-box-Binding Homeobox 1/genetics , Animals , Cell Line, Tumor , Cell Movement/genetics , Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation, Neoplastic/genetics , Humans , Mice , Neoplasm Invasiveness/genetics , Pancreatic Neoplasms/pathology , Xenograft Model Antitumor AssaysABSTRACT
Gluconeogenesis responses was assessed during a short starvation period and subsequent refeeding in Siberian sturgeon (Acipenser baerii) previously fed different dietary carbohydrates levels and experienced to a glucose stimuli during early life. The sturgeon larvae were previously fed either a high glucose diet (G) or a low glucose diet (F) from the first feeding to yolk absorption (8 to 12 d post-hatching [dph]). Each group of fish was sub-divided into 2 treatments at 13 dph and was fed either a high-carbohydrate diet (H) or a low carbohydrate diet (L) until 20 wk. In the current study, the fish in 4 groups (GL, FL, GH and FH) were experienced to starvation for 21 d following by re-feeding of their corresponding diets for 21 d. Fish were sampled at postprandial 6 and 24 h before starvation (P6h and P24h), starvation 7, 14 and 21 d (S7, S14 and S21) and 1, 7, 14 and 21 d during refeeding (R1, R7, R14 and R21). Plasma samples during refeeding were taken at P6h at each time point. Glycaemia levels, liver and muscle glycogen contents, activities and mRNA levels of hepatic gluconeogenic enzymes were examined. We found that both dietary carbohydrate levels and early glucose stimuli significantly affected the metabolic responses to starvation and refeeding in Siberian sturgeon (P < 0.05). During prolonged starvation, Siberian sturgeon firstly mobilized the liver glycogen and then improved gluconeogenesis when the dietary carbohydrates were abundant, whereas preserved the liver glycogen stores at a stable level and more effectively promoted gluconeogenesis when the dietary carbohydrates are absent to maintain glucose homoeostasis. During refeeding, as most teleostean, Siberian sturgeon failed controlling the activities and mRNA levels of phosphoenolpyruvate carboxykinase cytosolic forms (PEPCK-C), fructose-1,6-bisphosphatase (FBPase), but particularly controlled phosphoenolpyruvate carboxykinase mitochondrial forms (PEPCK-M) activities and mRNA expression of glucose-6-phosphatase (G6Pase, except in GL group). Siberian sturgeon has a full compensatory ability on growth, but this ability would be obstructed by early glucose stimuli when refeeding the low carbohydrate diet after S21.
