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

Abstract

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.

Polydatin suppresses nucleus pulposus cell senescence, promotes matrix homeostasis and attenuates intervertebral disc degeneration in rats

“…TNF‐α is able to induce more ROS to aggravate mitochondrial dysfunction characterized by lower mitochondrial membrane potential and less ATP production . MitoSOX fluorescence of NPCs was increased in the TNF‐α group compared with the control group, suggesting TNF‐α is capable of aggravating oxidative stress NPCs.…”

“…TNF-α is able to induce more ROS to aggravate mitochondrial dysfunction characterized by lower mitochondrial membrane potential and less ATP production. 10,26 MitoSOX fluorescence of NPCs was increased in the TNF-α group compared with the control group, suggesting TNF-α is capable of aggravating oxidative stress NPCs. After pretreatment of PD for 2 hours, the MitoSOX fluorescence decreased significantly compared with the TNF-α group, which indicated PD could facilitate ROS scavenge in NPCs (Figure 4A,B).…”

Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma

“…A recent study ( 12 ) opened a Pandora´s box for therapeutic options targeting the JNK signaling pathway, a major regulator of cell proliferation, against CCA. Earlier, several studies confirmed the critical role of the JNK signaling pathway in liver cancer.…”

“…( 9‐11 ) Importantly, JNK has lineage‐determinant functions in liver parenchymal cells (LPCs) where it not only favors proliferation of biliary cells but also directly biases biliary cell‐fate decisions in bipotential hepatic cells. It has been reported that JNK inhibition delays CCA progression ( 12 ) by impeding JNK‐mediating biliary proliferation. These data indicate that JNK modulation would be of therapeutic benefit in patients with CCA.…”

RPB5‐Mediating Protein Promotes Cholangiocarcinoma Tumorigenesis and Drug Resistance by Competing With NRF2 for KEAP1 Binding

“…Recently, a study found that hepatocyte‐specific Hspd1 knockout induced mitochondrial dysfunction, producing excessive ROS and causing cell damage that recruited macrophages to secrete tumor necrosis factor α (TNFα). TNFα/JNK (c‐Jun N‐terminal kinase)/c‐Jun signaling pathway activation promoted the development of hepatocytes with dual differentiation potential into cholangiocarcinoma . This finding indicates the important role of ROS in the development of cholangiocarcinoma.…”