Li Xinli, Liu Chun, Ip Blanche C, Hu Kang-Quan, Smith Donald E, Greenberg Andrew S, Wang Xiang-Dong
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.
J Exp Clin Cancer Res. 2015 Nov 11;34:138. doi: 10.1186/s13046-015-0254-2.
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.
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.
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.
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.
肿瘤进展位点2（TPL2）是一种丝氨酸 - 苏氨酸激酶，是炎症信号通路的关键调节因子，并介导致癌事件。Tpl2在非酒精性脂肪性肝病（NAFLD）相关肝细胞癌（HCC）发生发展中的潜在作用尚不清楚。
野生型和Tpl2基因敲除雄性小鼠在2周龄时经腹腔注射单剂量25mg·kg-1的肝致癌物（二乙基亚硝胺）启动，然后给予高碳水化合物饮食24周以诱导肝脂肪变性、炎症、腺瘤和肝癌。
与全部发生肝癌的野生型小鼠相比，Tpl2基因敲除小鼠的肝肿瘤发生率显著降低，且仅发生肝细胞腺瘤。Tpl2基因敲除小鼠的JNK和ERK磷酸化水平以及促炎细胞因子（Il-1β、Il-18、Mcp-1和Nalp3）的mRNA表达水平显著下调，这与肝脏炎症灶的发生率和数量减少相关。此外，Tpl2基因缺失导致肝脂肪变性以及从头脂肪生成相关标志物（ACC、SCD1、SREBP1C和AKT磷酸化）的表达降低，同时内质网应激生物标志物PERK和eIF-2α减少。
该研究首次揭示Tpl2通过其促炎作用在促进肝癌发生发展中起重要作用，提示Tpl2可能是肝癌预防的分子靶点。
