Bile acids are the end products

Bile acids are the end products of cholesterol catabolism and have also been considered as hepatomitogens. Recently, Yap has been shown to be activated by the mevalonate pathway, which is essential for the biosynthesis of isoprenoids and downstream cholesterol and bile acids (Sorrentino et al., 2014, Wang et al., 2014). The loss of both FXR and SHP led to enlarged livers, Yap activation, and spontaneous liver tumorigenesis (Anakk et al., 2013). Yap was shown to be important for bile duct and hepatocyte proliferation after cholestatic injury (Bai et al., 2012). These findings are in accordance with our data and support the interplay between bile acids and Yap. The bile glut 1 sequestrant cholestyramine resin binds to intestinal bile acids inhibiting their lipid solubilizing activity and bile acid reabsorption. This action causes a decrease in the bile acid pool. We found that bile acid depletion by cholestyramine abrogates Mst1/2-mutant-driven liver overgrowth and oncogenesis. Moreover, NTCP, a major bile acid transporter, was identified as an HBV entry receptor (Yan et al., 2012). HBV-bound NTCP could not transport bile acids, so chronic HBV infections cause cholestatic liver diseases, which eventually lead to HCC development (Oehler et al., 2014). A recent study showed that obesity-induced gut microbial bile metabolite changes promote liver cancer (Yoshimoto et al., 2013). Thus, it will be interesting to determine the role of gut microbial bile metabolite changes in bile acid-induced Mst1/2-deficient liver growth by transferring WT or Mst1/2 DKO fecal microbiota into Mst1/2-deficient germ-free mice. Taken together, our study revealed that enhancing bile acid metabolism by disrupting Hippo signaling could be a common occurrence and likely a pathogenetic factor in human HCC. The proper control of bile acid metabolism by therapeutically targeting FGF15-Hippo signaling might be crucial for liver growth control and cancer prevention.
STAR★Methods
Introduction The age and population distribution of the European Union countries and their developed economies are expected to change dramatically in the upcoming decades. Life expectancy is projected to increase from 78.3 years (2016) to 86.1 (2070) for males and from 83.7–90.3 for females. The total elderly % of the population (65 & over) in 2016 was 19.3% and by 2070 it is projected to be 28.8% [1]. This increase in the average lifespan leads to an increase of the total cost of aging, i.e. education, unemployment benefits, public spending on pensioners: healthcare and long-term daily care, for example [1]. Aging is a multi-faceted process characterized by a progressive decline of physiological functions, which in turn promote the prevalence of age-related diseases, sometimes stimulating chronic disease growth; thus, increasing long-term care costs. One of these diseases is cancer, whose prevalence increases with age. According to the National Cancer Institute, age is the highest single risk factor for cancer, this risk increasing significantly after the age of 50. Furthermore, the percentage of newly diagnosed cancer cases by age group is expected to be 14.1% (45–54 years), 24.1% (55–64) and 25.4% (64–74 years), in which half of all “new” cases occur after age 66. In this context, a number of reports have recently summarized the link between aging and cancer [[2], [3], [4], [5], [6], [7]]. Accumulation of mutations and aberrant cell proliferation are typical characteristics of cancer initiation, promotion and progression [8]. The aging decline of DNA damage-repair machinery, loss of immune system efficiency, along with chronic inflammation, increase of reactive oxygen species (ROS) and multiple mutations in the genes, can contribute to cancer development. For example, it has recently been reported that decrease of the immune system response to aging (age-related decline in T cells) could be a more relevant event in the risk of developing cancer than in multiple mutations of DNA during aging [9]. To obtain a better understanding of the connection between aging and cancer it is necessary to develop more effective approaches to cancer prevention and treatment. The study of cellular signaling pathways is becoming increasingly as important as that of molecular targeted therapy in cancer. Consequently, it is important to know the mechanisms involved in this pathway. In this review, we will summarize recent findings that link the Hippo pathway to aging and cancer.