Targeting of Tumor Suppressor GRHL3
by a miR-21–dependent Proto-oncogenic
Network Results in PTEN Loss and
Tumorigenesis
Despite its
prevalence, the molecular basis of
squamous cell carcinoma (SCC) remains
poorly understood. Evidence exists that
activation of Ras signaling, in concert
with inhibition of NF-kB function, is
sufficient for malignant transformation
of keratinocytes. Activated Ras
stimulates multiple effectors including
the RAF/MEK/ERK pathway, the
phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR
pathway, and the guanine nucleotide
exchange factors. An alternate mechanism
for activation of PI3K/AKT/mTOR
signaling in SCC is through loss of
expression of the phosphatase and tensin
homolog (PTEN) tumor suppressor gene.
PTEN acts as the most important negative
regulator of the PI3K pathway, and its
inactivation leads to increased activity
of the serine/threonine kinases, PDK1,
and AKT. Despite this, somatic
mutations, gene deletions, and promoter
hypermethylation of PTEN have not been
detected in human SCC, suggesting that
other mechanisms of inactivating the
gene may be involved in SCC
pathogenesis.
Earlier studies have shown that mice
lacking the Grainyhead-like 3 (GRHL3)
gene exhibit multiple epidermal
abnormalities. GRHL3 is a member of a
highly conserved family of transcription
factors critical for epidermal
development and homeostasis. In a recent
study published in Cancer Cell, Darido
et al. investigated the role of this
developmental transcription factor in
adult skin homeostasis and skin cancer
development.
Researchers identified GRHL3 as a potent
tumor suppressor in SCC in both humans
and mice and demonstrated that targeting
of GRHL3 by a miR-21–dependent proto-oncogenic
network underpins SCC in humans. They
defined PTEN as the critical downstream
effector of GRHL3 tumor suppressor
activity, providing the elusive
explanation for the low levels of PTEN
expression in SCC that occur in the
absence of genetic or epigenetic
alterations to the gene. In humans, a
miR-21 proto-oncogenic network
synchronously targets both tumor
suppressors GRHL3 and PTEN, leading to
amplification of PI3K/AKT/mTOR signaling
and induction of SCC of both skin, and
head and neck origins. Reduced levels of
GRHL3 and PTEN were evident in human
skin, and head and neck SCC, associated
with increased expression of miR-21.
Deletion of GRHL3 in adult epidermis
evoked loss of expression of PTEN, a
direct GRHL3 target, resulting in
aggressive SCC induced by activation of
PI3K/AKT/mTOR signaling. Restoration of
PTEN expression completely abrogated SCC
formation. This study defines the GRHL3–PTEN
axis as a critical tumor suppressor
pathway in SCC and demonstrates that
GRHL3/PTEN–deficient SCC displays an
oncogene addiction to the PI3K/AKT–signaling
pathway, with profound downregulation of
the MAPK/ERK pathway. Emerging from this
work is an increased rationale for the
use of direct inhibitors of PI3K/AKT/mTORC1
signaling and/or antagonists of miR-21
in the treatment of SCC.
Source:
Cancer Cell. 2011;20(5):635–648
The NOD-like Receptor NLRP12
Attenuates Colon Inflammation and
Tumorigenesis
Patients
with inflammatory bowel diseases (IBD)
such as Crohn’s disease and ulcerative
colitis are at increased risk for the
development of colorectal cancer.
Although the precise molecular mechanism
of IBD-related colorectal tumor
formation is incompletely understood, it
is widely viewed that chronic
inflammation shapes the tumorigenic
micro-environment in the gut by inducing
cytokines, chemokines, and other factors
through NF-kB, ERK, and STAT3 signaling.
Innate immune receptors such as
Toll-like receptors (TLR) at the surface
of epithelial cells and immune cells
initiate this inflammatory process by
activating the downstream transcription
factor NF-kB, which is a central
mediator of proinflammatory cytokine and
chemokine production. In addition to
TLRs, the immune system uses pattern
recognition receptors (PRRs) to induce
the production of inflammatory cytokines
in response to microbial components that
include C-type lectin receptors (CLRs),
RIG-I-like receptors (RLRs), HIN-200
proteins and nucleotide binding, and
oligomerization domain-like receptors
belonging to the NOD-like receptor (NLR)
family.
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NLRP12 is a
member of the intracellular NLR family,
which has been suggested to downregulate
the production of inflammatory
cytokines, but its physiological role in
regulating inflammation has not been
characterized. Zaki et al., in a study
published in Cancer Cell, analyzed mice
deficient in NLRP12 to study its role in
inflammatory diseases such as colitis
and colorectal tumorigenesis. They
showed that NLRP12-deficient mice are
highly susceptible to colon inflammation
and tumorigenesis, which is associated
with increased production of
inflammatory cytokines, chemokines, and
tumorigenic factors. Enhanced colon
inflammation and colorectal tumor
development in NLRP12-deficient mice are
due to a failure to dampen NF-kB and ERK
activation in macrophages.
This study demonstrates a regulatory
mechanism of intestinal inflammation and
tumorigenesis by
PRRs and paves the way to further
understanding the role of NLR proteins
in gastrointestinal disorders. This may
help identify new therapeutic approaches
to control inflammatory bowel diseases.
Source:
Cancer Cell. 2011;20(5):649–660
Genetic Activation of the MET Pathway
and Prognosis of Patients with
High-risk, Radically Resected Gastric
Cancer
Activation
of the MET/HGF pathway promotes
proliferative and anti-apoptotic
activities that are common to many
growth factors, but specifically, MET
activation demonstrated stimulation of
cell–cell detachment, migration, and
invasiveness. This pathway has been
found frequently expressed in gastric
carcinomas and is associated with a more
aggressive phenotype.
This background prompted Graziano et al.
to verify the hypothesis that MET
activation by gene copy number gain (CNG)
alone or in combination with the HGF
DATE (deoxyadenosine tract
element)–activating truncation may
promote a more aggressive gastric cancer
phenotype and poor prognosis. MET CNG of
five or more copies and homozygous HGF-truncated
DATE occurred in 10% and 13% patients,
respectively. Patients with MET CNG of
five or more copies (MET-positive)
showed significantly worse prognosis
with multivariate hazard ratio (HR) of
3.02 (95% CI: 1.71–5.33; P < 0.001) for
DFS and multivariate HR of 2.91 (95% CI:
1.65–5.11; P < 0.001) for OS. HGF-truncated
DATE did not show relevant prognostic
effect. The findings contribute to the
hypothesis that novel anti-MET therapies
could induce clinically relevant
anticancer effects in the subgroup of
patients with gastric cancer whose
tumors are MET positive (CNG of five
copies), or less likely, with HGF
homozygous DATE truncation and normal
MET CNG status. This information may
lead to the optimal development of these
compounds.
Source:
J
Clin Oncol. 2011;29(36):4789–4795
TFAP2E–DKK4 and Chemoresistance in CRC
Genomic and epigenetic alterations
of the gene encoding transcription
factor AP-2 epsilon (TFAP2E) are common
in human cancers. The gene encoding
dickkopf homolog 4 protein (DKK4) is a
potential downstream target of TFAP2E
and has been implicated in chemotherapy
resistance. Ebert et al. evaluated the
role of TFAP2E and DKK4 as predictors of
the response of CRC (colorectal cancer)
to chemotherapy and published the
findings in a recent issue of NEJM.
The expression, methylation, and
function of TFAP2E in CRC cell lines in
vitro and in CRC patients were analyzed.
TFAP2E was hypermethylated in 51%
patients in the initial cohort.
Hypermethylation was associated with
decreased expression of TFAP2E in
primary and mCRC specimens and cell
lines. DKK4 overexpression led to
increased fluorouracil chemoresistance
in CRC cell lines, whereas the
introduction of TFAP2E was associated
with increased sensitivity to
fluorouracil treatment. Data indicate
that fluorouracil-based chemotherapy is
largely ineffective in patients with CRC
with TFAP2E hypermethylation.
Specific targeting of DKK4 in these
individuals may, therefore, be an option
for overcoming TFAP2E-mediated
chemoresistance.
Source:
N
Engl J Med. 2012;366(1):44–53
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