Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Gene desert wikipedia , lookup
Genome evolution wikipedia , lookup
Cell-penetrating peptide wikipedia , lookup
Gene expression profiling wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
Silencer (genetics) wikipedia , lookup
Molecular evolution wikipedia , lookup
Point mutation wikipedia , lookup
Gene regulatory network wikipedia , lookup
Developmental Pathways in Hepatic Tumorigenesis: A -Catenin Perspective Satdarshan (Paul) Singh Monga, M.D. Wnt/-catenin signaling plays diverse roles in development and tissue homeostasis. In liver, it is important in multiple aspects of hepatic development where it controls hepatic induction, hepatoblast expansion and hepatocyte maturation. In adults, Wnt signaling is key to the process of metabolic zonation and is responsible for pericentral gene expression in a hepatic lobule. In addition spatio-temporally restricted Wnt/-catenin activation is crucial for normal hepatocyte proliferation observed during liver regeneration after surgical or toxicant-induced hepatic injury. On the other hand, untimely and sustained activation of -catenin mostly due to mutations or deletions affecting exon-3 of CTNNB1 or inactivating mutations or deletions in genes encoding for -catenin degradation components such as adenomatous polyposis coli gene or AXIN can result in hepatic tumorigenesis. Various liver tumors including hepatic adenomas, hepatoblastomas (HB) and hepatocellular cancers (HCC) exhibit such aberrations in Wnt signaling leading to nuclear translocation of -catenin. However, whether -catenin activation alone is sufficient to induce tumorigenesis or whether it cooperates with other signaling pathways to play a role in disease pathogenesis remains an important question. Using sleeping beauty transposon/transposase system, we address the role of -catenin and Hippo pathway. Hydrodynamic delivery of sleeping beauty constructs carrying Yap and -catenin genes in cis and transposase in trans yields HB in mice. This observation was validated in patients where around 80% of HB tissues showed simultaneous nuclear localization of -catenin and Yap. To further demonstrate the significance of -catenin in tumor biology, we use a chemical carcinogenesis model that yields HCC harboring activating point mutations in -catenin gene. Using locked nucleic acid antisense, we successfully targeted -catenin in this model, which in turn led to a notable decrease in hepatic tumorigenesis. Lastly, since -catenin is also a component of adherens junctions (AJ), we address if it is a druggable target. Indeed -catenin suppression led to -catenin upregulation at the membrane of liver cells both in vitro and in vivo. Concomitant suppression of -catenin and -catenin, however led to serious deleterious effects on hepatic biology that clearly mandates identification of mechanisms leading to -catenin compensation upon -catenin suppression. Thus -catenin plays an important role in hepatic tumorigenesis and its therapeutic inhibition in a subset of tumors will be of immense value.