Download a wnt-beta-catenin signaling perspective

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.