Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS.

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.

Relationship of fetal total bile acid and the change of fetal pancreas endocrine secretion and its impact on fetal growth and development in intrahepatic cholestasis of pregnancy / 中华妇产科杂志

Objective To investigate the relationship of fetal total bile acid (TBA) concentration with the change of fetal pancreas endocrine secretion and its impact on fetal growth and development in intrahepatic cholestasis of pregnancy(ICP). Methods The concentrations of TBA, insulin, glucagon and glucose in the cord blood were measured in 30 fetuses with maternal ICP (case group) and 30 fetuses of normogravidas(control group) after elective cesarean section during the same period in the Department of Obstetrics of Xiangya Second Hospital of Central South University from March 2007 to February 2008. The cord blood TBA concentration was investigated by enzyme method and the concentrations of insulin and glucagon were investigated by radioimmunoassay. The glucose was measured by oxidase-superoxide method. The neonatal weight, length and the ponderal index (PI) were measured after parturition. Results (1) The cord blood insulin concentration (9.0±3.3) mU/L and the ratio of insulin over glucagon 0. 048±0. 028 in the case group was significantly lower than that of controls(10.1±3.7) mU/L,0.050±0. 020 (P<0.05). The concentrations of TBA(10.3±3. 8)μmol/L and glucagon(235±57) ng/L in case group were obviously higher than that in controls (4.1±1.3)μol/L, (205±34) ng/L(P<0.05). But no difference was shown in the glucose concentration in cord blood between the ease and control groups [(3.4±1.1) mmol/L vs (3.6± 1.2 )mmol/L, P > 0.05]. (2)The neonatal weight and length in case group were significantly lower than that of control [(3163±478) g vs (3498±393)g, (46.5±2.3) cm vs (49.3±1.9)cm, P<0.01]; while the Ponderal index in ease group was significantly higher than that of control group (3.13±0. 23 vs 2. 92±0. 29,P <0.01). (3) The cord blood TBA concentration respectively showed a linear relationship with the cord blood insulin concentration, the cord blood glucagon concentration and the ratio of insulin over glucagon in the case group. With the increase in cord blood TBA concentration, the cord insulin concentration and the ratio of insulin over glucagon decreased; meanwhile the cord blood glucagon concentration rose(P<0.01). The cord blood insulin concentration and the ratio of insulin over glucagon in case group were respectively positively correlated with the neonatal weight and length, and were negatively correlated with the PI (P<0.01); while the cord glucagon concentration was respectively negatively correlated with the neonatal weight and length, and positively correlated with the P1 (P < 0.01 ).Conclusions In 1CP fetus pancreas, there are hypoinsulinism, glucagon oversecretion, and decrease of the ratio of insulin over glucagon, which is closely correlated with fetal TBA concentration. The endocrine function of fetal pancreas affects the fetal growth and development.