AXIN2: Tumor Suppressor, Oncogene or Both in Colorectal Cancer?
Gregory S. Yochum
Department of Biochemistry & Molecular Biology, The Pennsylvania State University College of Medicine, USA
*Corresponding author:
Gregory S. Yochum, Ph.D
Assistant Professor
Department of Biochemistry & Molecular Biology
The Pennsylvania State
University College of Medicine, USA E-mail: gsy3@psu.edu
Received July 20, 2012; Accepted July 23, 2012; Published July 25, 2012
Citation: Yochum GS (2012) AXIN2: Tumor Suppressor, Oncogene or Both in
Colorectal Cancer? J Cancer Sci Ther 4: xii-xiii. doi:10.4172/1948-5956.1000e109
The Wnt/β-catenin signaling pathway controls intestinal
homeostasis and is frequently deregulated in colorectal cancer (CRC)
(for a comprehensive review, see [1]). By tightly regulating the levels
and subcellular location of the β-catenin transcriptional co-activator,
the Wnt pathway governs cellular proliferation in the intestinal
crypt. Mutations in components of this pathway, most often in the
adenomatous polyposis coli (APC) tumor suppressor, are found
in approximately 90% of spontaneously arising CRCs. Moreover,
germline mutations in APC cause familial adenomatous polyposis
(FAP), an inherited cancer syndrome characterized by early onset of
colon adenomas. In the absence of a Wnt signal, cytoplasmic β-catenin
associates with a destruction complex of proteins containing APC,
glycogen synthase kinase 3 beta (GSK3β), casein kinase 1 (CK1) and
axis inhibitor proteins 1 and 2 (AXIN1 and AXIN2). Here, β-catenin
is phosphorylated and subsequently targeted for degradation by the
proteasome. An intact destruction complex ensures that Wnt/β-
catenin target genes are repressed in differentiated cells. In the presence
of Wnt, the destruction complex is inactivated, β-catenin protein
levels increase and β-catenin is translocated to the nucleus to drive
expression of growth-promoting genes including c-MYC and CCND1.
The APC mutations that commonly occur in CRC are believed, in part,
to render the destruction complex inactive resulting in deregulated
Wnt/β-catenin signaling and increased cellular proliferation. AXIN2
is a direct Wnt/β-catenin target gene and as such, it is thought to serve
in a negative feedback loop to ensure homeostatic levels of β-catenin.
The early and predominant model in the CRC field suggests AXIN2
is a tumor suppressor gene. In a survey of 105 tumor samples, Liu et al.
[2] found that 11 contained mutations in the AXIN2 gene that resulted
in premature stop codons. These mutations would be predicted to
promote oncogenesis by interfering with the ability of truncated AXIN2
to form a fully functional β-catenin destruction complex. However,
these samples contained wild-type APC and thus represented a small
fraction of CRC cases. It is therefore possible that AXIN2 may serve
an oncogenic role in the more common CRCs that harbor nonsense
mutations in APC.
Several studies over the years have either indirectly or directly
supported the hypothesis that AXIN2 is oncogenic. First, AXIN2
expression in FAP polyps and colon carcinomas is increased in
comparison to levels seen in uninvolved colonic mucosa [3,4]. Second,
a recent analysis of 287 established cells lines from various tissues
confirmed that AXIN2 mRNA levels are highest in lines derived
from colorectal cancers [5]. Third, AXIN2 promotes chromosome
instability-a process positively associated with oncogenesis [6]. Fourth,
AXIN2 association with centrosomes impairs the mitotic checkpoint
pathway [6,7]. Finally, AXIN2 knockdown diminished Wnt/β-catenin
signaling in an siRNA-based library screen [8]. These properties are not
in line with the notion that AXIN2 predominantly serves as a tumor
suppressor in CRCs.
A recent report in PNAS by Stephen Weiss’s group provides additional evidence supporting an oncogenic role of AXIN2 in CRC
[9]. In this compelling study, Wu et al. [9] found that AXIN2 stabilizes
levels of the Snail 1 transcriptional repressor in the nucleus. Snail 1
directly down-regulates E-cadherin expression thereby promoting
epithelial to mesenchymal transition (EMT). Tumor cells have
long been known to acquire an EMT phenotype as they metastasize
distant organs. A microarray analysis found that silencing AXIN2
expression in CRC cell lines decreased expression of mesenchymal
markers, such as vimentin and fibronectin, and increased expression
of epithelial markers including E-cadherin. Furthermore, as compared
to control cells, AXIN2-depleted CRC cells displayed greater migratory
properties in a cell invasion assay. Finally, silencing AXIN2 expression
reduced the number and size of lung metastases when these CRC cells
were injected into athymic nude mice. These new findings clearly
demonstrate that AXIN2 plays a pro-tumorigenic role in colon cancer
by promoting cellular metatasis.
AXIN2 functions as a tumor suppressor in some CRCs (i.e., when
APC is wild type), but functions as an oncogene in most CRCs (i.e.,
when APC is mutated). What implications do these reports have
for therapeutic management of this deadly disease? Several elegant
studies have identified the ADP-ribosylating enzymes, tankyrase 1/2,
as druggable targets (for a review, see [5]). Tankyrase transfers an
ADP ribose moiety to substrates including AXIN1 and AXIN2. ADPribosylated
AXIN1 and AXIN2 are subsequently ubiquitinated and
targeted for degradation by the proteosome. Small molecule inhibitors,
such as XAV939, IWRs and JW compounds, bind tankyrase with
high affinity and stabilize AXIN1 and AXIN2 proteins in CRC cells.
These compounds decrease β-catenin levels and reduce CRC growth
in vitro and in vivo. In light of recent work, stabilizing AXIN2 may
be detrimental as a therapeutic strategy. Therefore, efforts are required
to develop more specific tankyrase inhibitors that target AXIN1 and
not AXIN2. Alternatively, siRNA-based approaches designed to reduce
AXIN2 could be used in combination with tankyrase inhibitors to
improve the therapeutic outcome.
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