World Journal of Gastrointestinal Pathophysiology

Sherman AE et al . Sonic Hedgehog and gastric cancer
notype found in Drosophila embryos with a mutation in
the gene [5] . Three mammalian homologs have since been
discovered: Shh, Ihh and Dhh. Ihh and Dhh have mostly
tissue-specific expression while Shh has widespread expression
of which deficiency leads to neural, limb growth
and foregut defects [6] . Hedgehog is generated as a preprotein
before its signal sequence is cleaved, yielding
an approximately 45 kDa precursor. The precursor is
internally cleaved and a cholesterol moiety is attached to
a glycine residue on the nascent carboxy-terminus [7] . This
covalent attachment of cholesterol is a unique modification
among secreted ligands and is a requirement for
tissue specificity and localization of the molecule. In vertebrates,
Shh binds and inhibits Patched-1 (Ptc), consequently
activating Smoothened (Smo), which transduces
the Hedgehog signal into the cytoplasm, activating the
Gli family of transcription factors [8,9] . Despite this information,
the events leading to Gli activation, especially in
the mammalian stomach, are poorly understood.
Shh is a peptide morphogen produced in gastric
epithelium; however, expression in specific cell types
has been controversial. Recently, a study utilizing a Shh-
LacZ reporter mouse line identified all major cell lineages
of the corpus expressing Shh; these included surface
pit, mucous neck, zymogenic and parietal cells [10] . Some
stromal cells express signal transduction components
in addition to Shh; these include the 12-transmembrane
receptor, Ptc, Smo, 7-transmembrane receptor and Gli
transcription factor family. The Hedgehog ligand activates
Smo which leads to transcriptional activation of Gli1,
Gli2 becoming an activator and Gli3 no longer acting as a
repressor [11] . Therefore, Hedgehog signaling results in an
increase of activator Gli and a decrease in repressor Gli.
These events are crucial in the development and maintenance
of multiple organs and the role of Shh as a key
morphogen has been well documented [5,12] .
Shh has important roles in the development of multiple
organ systems including neuronal and gastrointestinal
systems [13,14] . Shh in the mammalian stomach has been
found to be hormonally regulated by gastrin and requires
an acidic environment for proper processing [15] . The acidactivated
pepsin A protease was found to mediate the
processing of the 45kDa precursor molecule to the active
Shh molecule. These findings indicate the importance of
the acidic gastric environment for maintenance of Shh in
the stomach.
Much of what we know about Shh’s role in mammals
has come from studies in animal models. Shh-knockout
mice display key features that support the importance of
proper Shh homeostasis for normal development and
physiological function.
Shh -/- mouse embryos displayed multiple gut abnormalities
including overt gut malrotation and intestinal
transformation of the stomach [16] . Additionally, neurons
of the enteric nervous system underwent abnormal differentiation
compared to wildtype. While this system provided
evidence for the role of Hedgehog in the coordination
of developmental genes, these mice die at or shortly
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after birth.
In order to study the effects of Shh signaling in the
stomach, Xiao et al [17] developed a mouse model expressing
a parietal cell-specific deletion of Shh (HKCre/
Shh KO ). This study found evidence of hypochlorhydria,
hypergastrinemia and foveolar hyperplasia by 8 mo of
age. Additionally, a delay in the differentiation of zymogen
cells, demonstrated by an increase in immature cells
expressing markers for both mucous neck and zymogen
cells, was documented in the stomach of HKCre/Shh KO
mice [17] . The deletion of Shh from parietal cells led to
alterations in stomach morphology and gastric cell differentiation;
however, there was no evidence of parietal cell
atrophy, a key step in the development of stomach cancer
in Helicobacter pylori (H. pylori) infection [18,19] . The absence
of parietal cell atrophy suggests that the loss of Shh expression
alone is not sufficient to trigger the development
of stomach cancer.
H. PYLORI INFECTION AND SONIC
HEDGEHOG
H. pylori infection is globally widespread and a major
cause of chronic atrophic gastritis with persistent infection
in 50% of the global population [20,21] . While infection
with H. pylori has been directly linked to the development
of gastric cancer, the mechanism of tumorigenesis is still
unclear. There are many factors that have been considered
in Helicobacter-mediated carcinogenesis; however, the
focus of this review will be to discuss its contribution by
modulating Shh expression. H. pylori infection primarily
contributes to gastric cancer development through two
mechanisms: loss of Shh by destruction of parietal cells
and induction of a chronic inflammatory gastric environment.
H. pylori and the inflammatory response
The ability of H. pylori to evade the primarily Th1-mediated
host immune response contributes to the development
of chronically elevated interleukin-1β (IL-1β) and
other inflammatory cytokines in the stomach [10,22] . A study
of H. pylori associated with chronic atrophic gastritis
found upregulation of a gene encoding cysteine-rich protein
A, which induces Th1 cytokines interferon (IFN)-γ
and IL-12 [23] . Additionally, H. pylori-associated atrophic
gastritis has been found to be more frequent in patients
with pro-inflammatory polymorphisms of genes for IL-
1β and tumor necrosis factor (TNF)-α [24,25] . Specifically, it
has been shown that elevated IL-1β leads to the suppression
of Shh, which is necessary for the growth and differentiation
of the gastric mucosa during cell restitution
during H. pylori infection [10,26] .
Loss of Shh during chronic inflammation
The loss of parietal cells through Helicobacter infection and
subsequent autoimmunity has been well documented [22,27] .
Molecular mimicry between the H + ,K + -ATPase local-
104 December 15, 2011|Volume 2|Issue 6|