4 During the 1990s, evidence of a linkage between OCs and hepatocellular carcinoma (HCC) increased with experimental proof. Dunsford and Sell5 and Hixson et al.6 attempted to analyze the phenotypic relationships between OCs, bile duct cells, and adult and fetal cells. They found that OCs, preneoplastic foci, early tumor nodules, and primary HCC express both OC and hepatocyte antigens. This suggests a cause-effect relationship between OCs and HCC. Their results corroborated

the idea that OCs appear and proliferate in the liver as previously reported by Farber7 and Hewitt8 in the late 1950s, and they were confirmed by Dumble et al.9 nearly a half-century later. Rodent models of liver tumorigenesis have been based on chemical induction, which yields HCC almost exclusively and cholangiocarcinoma PLX3397 datasheet (CC) only rarely. Unfortunately, animal models of CC have been limited www.selleckchem.com/products/chir-99021-ct99021-hcl.html primarily to the Syrian hamster model, murine models of gallbladder adenocarcinoma, and the administration of furan to rats.10 Thus, liver-specific neurofibromatosis type 2 (Nf2−/−)–deleted mice11 not only represent an excellent model of liver

tumorigenesis for both HCC and CC but also offer an excellent tool for studying the involvement of OCs in liver malignancies. These mice develop a great variety of histopathological types of HCC (including trabecular, solid, pseudoductular,

and acinar HCC) and early CC that resemble human tumorigenesis.11 NF2 is an inherited disorder characterized by the development of Schwann cell tumors of the vestibulocochlear nerve. Several tumors of the nervous system, including schwannomas, meningiomas, and ependymomas, have been associated with mutations in the NF2 locus.12 The NF2 gene codes for a 595–amino acid protein called Merlin; Merlin is highly related to the ezrin, radixin, FER and moesin proteins, which are actively involved in the regulation of the cytoskeleton and signal transduction pathways.13 Merlin caught the attention of cancer researchers because it was found to be a negative regulator of the Hippo/Warts/Yorkie tumor suppressor pathway in Drosophila. However, the function of Merlin in the regulation of the analogous macrophage stimulating 1 (Mst)/large tumor suppressor (Lats)/yes-associated protein (Yap) pathway in mammals is not clear yet.14 In the actual study, McClatchey’s group11 used different experimental approaches to investigate whether NF2/Merlin regulates Mst/Lats/Yap. They observed that the absence of NF2/Merlin does not change the phosphorylation, localization, or expression of Yap1-related genes after the endogenous or exogenous administration of Merlin or short hairpin RNA knockdown in liver-specific NF2-deleted OCs.