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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #331334
Research Project: Molecular Targets of Tomato Carotenoids and their Metabolites in Cancer Prevention

Location: Jean Mayer Human Nutrition Research Center On Aging

Title: Tumor progression locus 2 ablation suppressed hepatocellular carcinoma development by inhibiting hepatic inflammation and steatosis in mice

Author
item LI, XINLI - Medical College Of Soochow University
item LIU, CHUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item IP, BLANCHE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item HU, KANG QUAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item SMITH, DONALD - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item GREENBERG, ANDREW - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Experimental and Clinical Cancer Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/4/2015
Publication Date: 11/11/2015
Citation: Li, X., Liu, C., Ip, B.C., Hu, K., Smith, D.E., Greenberg, A., Wang, X. 2015. Tumor progression locus 2 ablation suppressed hepatocellular carcinoma development by inhibiting hepatic inflammation and steatosis in mice. Journal of Experimental and Clinical Cancer Research. 34:138. doi: 10.1186/s13046-015-0254-2.

Interpretive Summary: Tumor progression locus 2 (TPL2), which is an enzyme, functions as a critical regulator of inflammatory pathways and mediates cancer development. This study revealed for the first time that Tpl2 plays a significant role in promoting liver cancer development by its pro inflammatory effect, which suggested that Tpl2 could be a molecular target for liver cancer prevention.

Technical 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 downregulated phosphorylation of JNK and ERK, and levels of mRNA expression of pro-inflammatory cytokines (Il-1beta, 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. Conclusion: 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.