Gastric cancer is the fourth most common cancer and the third leading cause of
cancer-related deaths worldwide, with an estimated 951,600 new gastric cancer cases
and 723,100 deaths occurred in 2012.[1,2]. Despite a steady decline in incidence and
mortality of gastric cancer have been observed in past decades, the prognosis in gastric
cancer remains poor, because high proportion of people are diagnosed at late stage. In
gastric cancer, poor prognosis is associated with late TNM stage. The overall
5-year relative survival rate of gastric cancer patients with stage IV in the United States
was only about 4%.
Treatments of gastric cancer are according to stage and patients’ general health. The
major treatment is surgery, but when patients can’t undergo surgery or recurrence
happens after surgery, it needs other treatments, including chemotherapy, radiotherapy
and target therapy.[3]
1-2. Mucin-type glycosylation
Introduction
Glycosylation is the most common post-translational modification of proteins. It
refers to the process that attaches glycans to proteins, lipids, or other organic
molecules. There are two major types of glycosylation: N-linked and O-linked
glycosylation. The most common type of O-glycosylation is mucin-type
O-glycosylation, which forms the GalNAc1-O-Serine/threonine linkage. This process is
initiated by a large family of polypeptide GalNAc transferases (GALNT), consisting of
at least 20 members in humans, namely GALNT1 to 20.[4]
Role of glycosylation in cancers
Glycobiology has become a focus of research in cancer biology.[5] Aberrant
glycosylation may be owing to under-/overexpression of glycosyltransferases or
mislocalization of glycosyltransferases. Glycans have been found to participate in
numerous fundamental biological processes involved in cancer, such as inflammation ,
immune surveillance, cell–cell adhesion, cell–matrix interaction, inter- and intracellular
signaling, and cellular metabolism. [6]
Common feature of tumors is the overexpression of truncated O-glycans, such as the
disaccharide Thomsen–Friedenreich antigen (T antigen) and the monosaccharide
GalNAc (also known as Tn) and their sialylated forms (ST and STn).[7]
Dysregulation of GALNTs has been found in many cancers and plays a critical role
in cancer development. For instance, GALNT3 expression significantly correlated with
shorter progression-free survival (PFS) intervals in epithelial ovarian cancer (EOC)
patients with advanced disease.[8] GALNT6 is upregulated in breast cancer and might
contribute to mammary carcinogenesis through aberrant glycosylation and
stabilization of MUC1[9] In addition, GalNT14 is overexpressed in colorectal
carcinoma and pancreatic cancer and is associated with altered sensitivity to
TRAIL-induced apoptosis through modulation of the O-glycosylation of death
receptors on these tumor cells. It has been reported that GALNT3, GALNT6 and
GALNT10 were biomarkers associated with lymph node metastasis[10], venous
invasion[11] and poor differentiation of gastric cancer[12] respectively. In vitro studies
have shown that knockdown of GALNT2 increases cell proliferation and invasion in
gastric cancer[13] and hepatocellular carcinoma.[14], but decreases migration and
invasion of oral squamous cell carcinoma.[15] In our previous study, we found that low
GALNT2 expression correlated with increased tumor depth, lymph node metastasis, and
TNM stage and shorter disease-free survival and downregulation of GALNT2 enhances
malignancy of gastric cancer through increasing MET phosphorylation. Understanding
the mechanisms and consequences of variations in glycosylation associated with
neoplastic disease will provide important insight into neoplastic progression
1-3. Epidermal growth factor receptor (EGFR)
The epidermal growth factor receptor (EGFR) is a 170 kDa receptor containing
approximately 20% of carbohydrate of its molecular mass and is heavily N-glycosylated.
EGFR is consisting of an extracellular ligand binding domain (domains I-IV), a
transmembrane region, an intracellular domain with tyrosine kinase activity, and a tail
containing tyrosine residues, required for downstream signaling. Ligand binding brings
two receptor monomers together and allows for the dimerization and subsequent
activation of the kinase domain. EGFR activation leads to receptor phosphorylation and
initiates diverse downstream signaling pathways including the RAS/RAF/MAP kinase
and PI3K/Akt/mTOR signaling networks, which play a vital role in several critical
cellular processes including proliferation, motility, and invasion.[16]
EGFR and cancers
Dysregulation of EGFR has been observed in variety of cancer, including breast
cancer, colorectal cancer and non-small cell lung carcinoma (NSCLC), etc. In NSCLC,
overexpression of EGFR or mutations in intracellular EGFR have been observed in
43-89% of cases.[17] In breast cancer, EGFR overexpression is associated with
large tumor size, poor differentiation, and poor clinical outcomes. Many therapeutic
agents targeting EGFR have been under clinical trial.[18-20] Studies observed that
EGFR-positive rate was 14-44% in gastric cancer. However, the correlation between
EGFR and clinic-pathological characteristics was controversial. EGFR-positive was
correlated with advanced TNM stage, lymph node metastasis, vascular invasion and
shorter progression-free-survival (PFS).[21-25], but Fuse et al. found there was no
correlation between EGFR expression and overall survival rate. [26] In vitro
experiments showed that EGFR activation and its downstream signaling PI3K-Akt
pathway were required in gastric cancer migration, and treated with EGFR inhibitor or
PI3K inhibitor could suppress the migration ability.[27] In addition, knockdown of
EGFR suppressed cell growth, invasion and induced cell apoptosis and cell cycle arrest
in gastric cancer through Akt pathway.[28]
Aside from studying expression of EGFR in cancer and its role in cancer progression,
many studies have focused on investigating correlation between
phosphorylated-EGFR(p-EGFR) and clinical outcomes, because EGFR is a receptor
tyrosine kinase, it becomes activated only when it’s phosphorylated. In current studies,
the prognostic significance of p-EGFR on clinical outcomes has been reported in many
cancers, such as breast cancer, NSCLC. [29-31] Zhang et al. reported that p-EGFR was
detected in 83.3% of gastric cancer and it correlated with T stage.[32] The prognostic
impact of p-EGFR remains unknown, so it needs further studies to confirm. These
findings would be beneficial for predicting prognosis or providing new target for
treatment.