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

Li X, Liu C, Ip BC, Hu KQ, Smith DE, Greenberg AS, Wang XD - J. Exp. Clin. Cancer Res. (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

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.

No MeSH data available.


Related in: MedlinePlus

Representative pathologic lesions in livers. Hepatic lesions were assessed by H&E staining. Upper panel: Normal (Left); Steatosis and inflammatory foci (Right); Middle Panel: Hepatocellular adenoma (low magnification at x 25 and x100); Lower panel: HCC (low magnification at x25 and x200)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4642781&req=5

Fig1: Representative pathologic lesions in livers. Hepatic lesions were assessed by H&E staining. Upper panel: Normal (Left); Steatosis and inflammatory foci (Right); Middle Panel: Hepatocellular adenoma (low magnification at x 25 and x100); Lower panel: HCC (low magnification at x25 and x200)

Mentions: Tpl2 knockout mice had significantly lower liver weight and final body weight than those of wild-type control, although there had no significant difference in the ratio of liver weight/body weight between two groups (Table 1). The tumor incidence on the surface of liver in Tpl2 knockout mice was significantly lower than wild-type mice (75 % vs 100 % respectively, P < 0.05, Table 1). The number of hepatic tumor had no statistical difference between those two groups. The pathological analysis demonstrated that all wild-type mice (26 out of total 26 mice) developed hyperplasia, hepatocellular adenoma (Fig. 1c, 1d) and HCC (Fig. 1e, 1f) after the 24-week HCD feeding (Table 1). In contrast, the Tpl2 knockout mice with positive tumor on the surface of the liver (15 out of 20) developed only hyperplasia and hepatocellular adenoma, and no HCC detected (Table 1).Table 1


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

Li X, Liu C, Ip BC, Hu KQ, Smith DE, Greenberg AS, Wang XD - J. Exp. Clin. Cancer Res. (2015)

Representative pathologic lesions in livers. Hepatic lesions were assessed by H&E staining. Upper panel: Normal (Left); Steatosis and inflammatory foci (Right); Middle Panel: Hepatocellular adenoma (low magnification at x 25 and x100); Lower panel: HCC (low magnification at x25 and x200)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4642781&req=5

Fig1: Representative pathologic lesions in livers. Hepatic lesions were assessed by H&E staining. Upper panel: Normal (Left); Steatosis and inflammatory foci (Right); Middle Panel: Hepatocellular adenoma (low magnification at x 25 and x100); Lower panel: HCC (low magnification at x25 and x200)
Mentions: Tpl2 knockout mice had significantly lower liver weight and final body weight than those of wild-type control, although there had no significant difference in the ratio of liver weight/body weight between two groups (Table 1). The tumor incidence on the surface of liver in Tpl2 knockout mice was significantly lower than wild-type mice (75 % vs 100 % respectively, P < 0.05, Table 1). The number of hepatic tumor had no statistical difference between those two groups. The pathological analysis demonstrated that all wild-type mice (26 out of total 26 mice) developed hyperplasia, hepatocellular adenoma (Fig. 1c, 1d) and HCC (Fig. 1e, 1f) after the 24-week HCD feeding (Table 1). In contrast, the Tpl2 knockout mice with positive tumor on the surface of the liver (15 out of 20) developed only hyperplasia and hepatocellular adenoma, and no HCC detected (Table 1).Table 1

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

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.

No MeSH data available.


Related in: MedlinePlus