Papel de las C-JUN cinasas N-terminales (JNK) en el desarrollo de cáncer de vías biliares

Resumen

Hyperplasia of the biliary epithelia with variable atypia in cystic bile ducts such as the one occurring may give rise to malignant transformation. In fact, Caroli¿s disease (CD), a rare congenital disorder characterized by non-obstructive segmental saccular dilatation of the large intrahepatic bile ducts, is an etiological factor for the development of intrahepatic cholangiocarcinoma (CCA). CCA is an epithelial neoplasm derived from primary and secondary bile tracts, and accounts for 5¿10% of primary liver cancer, whose incidence and mortality are steadily increasing. The 5-year survival of patients with CCA remains unacceptably low, and survival has not dramatically improved in the past 20 year. This is in part due to a lack of understanding of the pathophysiological mechanisms underlying CCA. Since biliary tract cancer is often diagnosed late, the success of the only curative procedure - surgical resection - is very limited, and the lack of biomarkers or diagnostic tools which would lead to early diagnosis is a matter of concern. Very recently, we described that in primary sclerosing cholangitis (PSC), a cholestatic liver disease characterized by fibrosing inflammatory damage of the biliary tree, and a risk factor for CCA, JNK1/2 activation is a main trigger of disease progression. Additionally, it was reported that JNK inhibition delays CCA progression by impeding JNK-mediating biliary proliferation. In this case, we hypothesize that the synergistic dysfunction of Jnk1/2 in hepatocytes drives the development of cholangiocarcinogenesis. Mice with specific deletion of Jnk1/2 in hepatocytes (Jnk¿hepa) and floxed (Jnkf/f) control mice were fed and sacrificed at different time points during liver disease progression. Likewise, different toxicity treatments (including TAA, DEN/TAA and DEN/CCl4) experimental models were also used. All livers and serums were harvested at the exact time points according to different treatments. Histopathological examination of livers, immunofluorescence and immunohistochemistry, protein expression and Real-Time quantitative Reverse Transcription PCR (qRT-PCR) studies were performed at the same time. Also, we have showed that other MAPKs have shown potential to be considered as therapeutic targets not only in CCA but also in other types of cancer. Altogether, these data indicate that JNK modulation would be of therapeutic benefit in CCA patients. Nevertheless, little is known about the cell-type specific role and mechanism of JNK in biliary overgrowth in order to have a targeted and definitive therapy against CCA. Yet, it remains unknown the real contribution of ER stress to the progression of CCA. Importantly JNK activation occurs in response to ER stress. Evidence suggests that two functionally distinct phases of JNK signaling exist in the ER stress response ¿ an early prosurvival and a late stage which promotes cell death. Additionally, it has been indicated that the JNK signaling pathway might modulate the induction of ER stress during human cholangiocarcinogenesis. ER stress can be transmitted to mitochondria dysfunction and degradation ¿ a phenomenon known as mitophagy - in association with different pathologies. Altogether, this set of data suggests that JNK function is pivotal to modulate ER stress induction leading to mitochondria dysfunction, which, in turn, would create a favorable niche for hyperproliferation of the biliary epithelium and CCA development.