title: Tumor progression locus 2 ablation suppressed hepatocellular carcinoma development by inhibiting hepatic inflammation and steatosis in mice.
abstract: BACKGROUND
  Tumor progression locus 2 (TPL2), a serine-threonine kinase, functions as a critical regulator of inflammatory pathways and mediates oncogenic events. The potential role of Tpl2 in nonalcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) development remains unknown.
  
  
  METHODS
  Both wild-type and Tpl2 knockout male mice were initiated by a hepatic carcinogen (diethylnitrosamine, i.p. with a single dose of 25 mg.kg(-1))at 2 weeks of age, and then were given the high carbohydrate diet feeding to induce hepatic steatosis, inflammation, adenoma and HCC for 24 weeks.
  
  
  RESULTS
  Tpl2 knockout mice had significantly lower incidences of liver tumor and developed hepatocellular adenoma only, which is contrast to wild-type mice where they all developed HCC. Tpl2 knockout mice had significantly down-regulated phosphorylation of JNK and ERK, and levels of mRNA expression of pro-inflammatory cytokines (Il-1β, Il-18, Mcp-1 and Nalp3), which correlated with the reduced incidence and number of hepatic inflammatory foci. Furthermore, Tpl2 ablation resulted in decreased hepatic steatosis and expression of de novo lipogenesis related markers (ACC, SCD1, SREBP1C and AKT phosphorylation), as well as reduction of endoplasmic reticulum stress biomarkers PERK and eIF-2a.
  
  
  CONCLUSIONS
  The study revealed for the first time that Tpl2 plays a significant role in promoting HCC development by its pro-inflammatory effect, which suggested that Tpl2 could be a molecular target for HCC prevention.
authors.affiliation: Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA, 02111, USA.|School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, 215123, PR China.
authors.forename: Xinli
authors.initials: X
authors.lastname: Li
authors.affiliation: Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA, 02111, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Liu
authors.affiliation: Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA, 02111, USA.
authors.forename: Blanche C
authors.initials: BC
authors.lastname: Ip
authors.affiliation: Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA, 02111, USA.
authors.forename: Kang-Quan
authors.initials: KQ
authors.lastname: Hu
authors.affiliation: Comparative Biology Unit, Boston, MA, USA.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Smith
authors.affiliation: Obesity and Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, 02111, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Greenberg
authors.affiliation: Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA, 02111, USA. xiang-dong.wang@tufts.edu.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Wang
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005234:Fatty Liver / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006505:Hepatitis / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis / Q000235:genetics; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D011518:Proto-Oncogene Proteins; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human