Correlation of SKP2 expression and H.

Pylori
infection in Gastric carcinoma.

Introduction:

Stomach cancer is the third leading cause of cancer death in

both sexes worldwide (723,000 deaths, 8.8% of the total)

making it the fifth most common malignancy in the world, after

cancers of the lung, breast, colorectal and prostate. Gastric

cancer is heterogeneous disorders. Genetic factors, H. pylori

infection and various environmental factors contribute to its

development. Advanced atrophic corpus-predominant gastritis

provides the histological base for its genesis. Low socio-

economic status and poor hygienic conditions, smoking habits,

heavy alcohol consumption, high salt and low intake of

vegetables and fruits are important external factors for the

occurrence of gastric cancer.

Fig. 1.1 Graph shows the estimated gastric cancer age-

standardized incidence and mortality rates per 100,000

(reproduced from

http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx) .
Advanced gastric cancer can be classified by its common

macroscopic characteristics into following four main types as

proposed by Borrmann in 1926.

Type I Polypoid

Type II Fungating

Type III Ulcerated

Type III Diffusely Infiltrative

This is a rather a classic system, but it has been used by many

investigators as the standard for the macroscopic classification
of advanced gastric cancer, owing to its usefulness for both
clinical and research purposes. Later it was redesigned by
Japanese Research Society for Gastric Cancer into more
systemic one. A gross morphologic classification of early gastric
carcinoma into five groups has been formulated and is now used
internationally.
1. Type I: Protruded

2. Type IIa: Elevated

 3. Type IIb: Flat

4. Type IIc: Depressed

5. Type III: Excavated

Epidemiological Studies have implicated that colonization of

the stomach by Helicobacter pylori is a risk for various
development of gastric diseases including gastric cancer. In
1994, the International Agency for Research on Cancer and The
World Health Organization classified Helicobacter pylori
(Figure 1.2) as a type I carcinogen, but the exact mechanism
leading to gastric carcinoma is not clearly understood. The
effects of H. pylori infection on gastric cancer appear
multifactorial, involving host and environmental factors as well
as differing bacterial strains. H. pylori is most closely associated
with intestinal gastric cancers, which follow a stepwise pathway
toward malignancy, similar to that in the colon. In the Correa
model of gastric carcinogenesis, gastric inflammation leads to
mucosal atrophy, metaplasia, dysplasia, and, ultimately,
carcinoma . Studies have shown that H. pylori infection is an
independent risk factor for distal gastric cancer, with a 3- to 6-
fold increased risk relative to those without the infection .
However, the great majority of infected individuals will never
develop gastric neoplasia: approximately 40% of patients
infected with H. pylori will develop gastric metaplasia but fewer
than 1% will develop cancer . More direct evidence implicating
H. pylori as a gastric carcinogen has come from the
demonstration of gastric cancer in the Mongolian gerbil
following experimental infection by H. pylori and from
C57/BL6 mice infected with the related gastric bacterium H.
felis. How H. pylori promotes gastric carcinogenesis is not
known. However, studies in humans and in animal models have
demonstrated that H. pylori increases the percentage of gastric
mucosal epithelial cells displaying markers of proliferation and
apoptosis .
A

B
Figure 1.2 Helicobacter pylrori. (a) Scanning electron

micrograph image showing the wavy, thin, rod-shaped

bacterium attached to the foveolar epithelium of the stomach.

(b) Schematic diagram depicting the virulence factors of

Helicobacter pylori, cagA, cytoxin associated gene A.

Gastritis is defined by inflammation of the stomach lining

associated with mucosal injury. The duration of mucosal
inflammation can be used to separate this condition from acute
gastritis and chronic active gastritis. H. pylori is the most
common infectious etiology associated with gastritis.
The majority of patients infected with H. pylori develop acute
gastritis which may spontaneously resolve. The ability of H.
pylori to cause acute gastritis is best demonstrated from studies
where healthy volunteers have been intentionally infected with
the organism. This acute infection is associated with the
development of hypochlorhydria and neutrophilic infiltration on
gastric biopsy . After an acute H. pylori infection, the majority
of acute gastritis evolves into chronic active gastritis that is
histologically characterized by mononuclear cells,
predominantly lymphocytes, plasma cells and macrophages.
Lymphoid follicles with germinal centers are frequently seen
and are characteristic of an H. pylori infection . Three types of
chronic gastritis are recognized: pan gastritis, antrum
predominant, and corpus predominant. Diffuse antral gastritis
with normal or increased acid secretion. This is associated with
little or no gastric atrophy and duodenal ulcers (DUs). Persistent
inflammation results in the development of gastric atrophy with
hypo-chlorhydria, or achlorhydria . These changes facilitate the
proximal migration of the bacteria, leading to corpus or
multifocal gastritis, which tends to progress through intestinal
metaplasia, then to intestinal type GC.

S-phase kinase-associated protein-2 (Skp2) is overexpressed in

human cancers and associated with poor prognosis. Skp2 acts as
an oncogenic protein by enhancing cancer cell growth and
tumor metastasis .
S-phase kinase-associated protein 2 (Skp2), a member of F-box

protein family, is the substrate recognition subunit of Skp1-

Cullin-F box protein (SCF) E3 ubiquitin ligase complex . Early

reports demonstrated that Skp2 recognizes and targets cell cycle

inhibitors p21Cip1/WAF and p27Kip1, leads to their ubiquitination and

degradation, and further causes cell cycle progression . Skp2 is

overexpressed and associated with poor prognosis in variety of

human cancers, including prostate cancer , gastric cancer, breast

cancer , and liver cancer , suggesting the oncogenic role of Skp2

in tumorigenesis.

Recent studies show that Skp2 promotes cancer progression by

enhancing cell growth, inhibiting apoptosis, regulating the cell

cycle, promoting invasion and metastasis, inducing drug

resistance, and participating in cross-talk with other major

cancer signaling pathways. Skp2-transfected gastric cancer cells

are resistant to actinomycin D-induced apoptosis .

Many studies have been done on several kinds of human

malignancies including Gastric cancer to show the relation of

Skp2 in tumorigenesis. Most of the studies have been done to

predict the relation of Skp2 with disease prognosis. Some has

stated Skp2 as an independent factor in the prediction of

prognosis . On contrary, another studies has focused Skp2 as the

dream target in the coming age of cancer therapy . Not many

articles have compared the Skp2 expression in Gastric cancer in

relation with Helicobacter Pylori infection.

All these results regarding Skp2 expression in Gastric cancer in

relation with Helicobacter pylori makes it an interesting topic

for restudy. In this research, I am going to study the expression

of Skp2 and Helicobacter pylori infection in the progression of

Gastric Cancer. As these two factors are involved in two

different pathways of apoptosis, I will compare their

expressions as well to see if there is any significant dominance

of one on the other, and will also study their relation with other

clinicopathological parameters.
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