Syndecan-1 expression in human glioma is correlatedwith advanced tumor progression and poor prognosis

Yimin Xu • Jun Yuan • Ziheng Zhang •

Lvbiao Lin • Shengliang Xu

Received: 20 March 2012 / Accepted: 7 June 2012 / Published online: 20 June 2012

� Springer Science+Business Media B.V. 2012

Abstract Syndecan-1 has been implicated in tumorigen-

esis and progression of various human malignancies. Recent

studies have demonstrated that syndecan-1 may have a dif-

ferent function and biological activity depending on the

specific tumor type. Therefore, the aim of this study was to

investigate the clinical significance of syndecan-1 in human

gliomas. One hundred and sixteen glioma patients (26 World

Health Organization (WHO) grade I, 30 WHO grade II, 30

WHO grade III, and 30 WHO grade IV) and 15 normal brain

specimens acquired from 15 patients undergoing surgery for

epilepsy as control were collected. Immunohistochemistry

assay, quantitative real-time PCR and Western blot analysis

were carried out to detect the expression of syndecan-1 at

gene and protein levels in glioma samples with different

WHO grades. Syndecan-1 gene and protein levels were both

higher in glioma tissues compared to controls (both P \0.001). In addition, its expression levels increased with

ascending tumor WHO grades according to the results of

immunohistochemistry assay, quantitative real-time PCR

and Western blot analysis. Moreover, the survival rate of

syndecan-1-positive patients was significantly lower than

that of syndecan-1-negative patients (P = 0.006). We fur-

ther confirmed that the increased expression of syndecan-1

was an independent prognostic indicator in glioma by mul-

tivariate analysis (P = 0.01). Our data suggest for the first

time that the increased expression of syndecan-1 at gene and

protein levels is correlated with advanced tumor progression

and poor outcome in patients with glioma. Syndecan-1 might

serve as a potential prognosis predictor of this dismal tumor.

Keywords Glioma � Immunochemistry assay �Prognosis � Quantitative real-time PCR � Syndecan-1 �Western blot analysis

Introduction

Human glioma is the most common type of primary brain

tumors worldwide. It occurs in any age, sex, or ethnicity.

Ionizing radiation and rare genetic syndromes have been

identified as definitive risk factors for this tumor [1].

According to the World Health Organization (WHO)

guidelines [2], gliomas are histologically classified into

four grades: pilocytic astrocytoma (grade I), diffuse

astrocytoma (grade II), anaplastic astrocytoma (grade III)

and glioblastoma multiforme (GBM, grade IV). Among

these, the relatively slower-growing WHO I–II lesions are

referred to as low-grade gliomas and the more rapidly

growing WHO III–IV lesions are referred to as high-grade

gliomas. Both diagnostic technologies and therapeutic

strategies have been greatly advanced, but no cure for

glioma exists and, most patients die of this tumor. Espe-

cially in China, the 5-year survival rates of low-grade

(grade I–II) and high-grade (grade III–IV) glioma patients

are: 75.4 and 18.2 %, respectively [3]. Several traditional

clinical parameters, such as patients’ age, preoperative

duration of symptoms, WHO grade, Karnofsky perfor-

mance status (KPS) score, tumor necrosis, surgical resec-

tion extent, and use of postoperative radiation therapy,

have been used to evaluate the prognosis of patients with

gliomas. However, because of the heterogeneous of glio-

mas, these clinical parameters do not fully account for the

observed variation in survival rates [4]. Similar with

other tumors, there are various genetic factors which con-

tribute to the development and progression of gliomas.

Y. Xu � J. Yuan (&) � Z. Zhang � L. Lin � S. Xu

Department of Neurosurgery, First Affiliated Hospital

of Medical College, Shantou University, Shantou 515041,

Guangdong Province, China

e-mail: yuan_junst@163.com

123

Mol Biol Rep (2012) 39:8979–8985

DOI 10.1007/s11033-012-1767-9

Understanding the aberrant alterations of oncogenes and

tumor suppressor genes is necessary to improve the diag-

nostic efficiency and to develop novel targeted approaches

for management of gliomas.

The mammalian syndecan family of cell surface heparan

sulfate proteoglycans contains four members, each encoded

by distinct genes [5]. Syndecans interact with a wide variety

of proteins, including growth factors and extracellular matrix

(ECM) constituents by their heparan sulfate glycosamino-

glycan chains. Consequently, they participate in a variety of

cellular processes, including cell proliferation, cell adhesion,

cell migration, cell–cell and cell–matrix interactions [6].

Syndecan-1, also known as CD138 and as the most exten-

sively studied member of the syndecan family, is expressed

primarily by epithelial cells and leucocyte subpopulations in

healthy adult tissue [7]. The syndecan-1 core protein con-

tains highly conserved transmembrane and cytoplasmic

domains, which mediate oligomerization and interact with

the cytoskeleton; the extracellular domain harbors attach-

ment sites for heparan sulfate, as well as chondroitin sulfate

chains, which are linear polymers of repetitive disaccharide

units of uronic acids and variably sulfated N-acetylgluco-

samine or N-acetylgalactosamine, capable of forming

specific ligand-binding motifs [8]. Recent studies have

demonstrated that syndecan-1 plays important roles in tumor

progression of a variety of human malignancies [9–12].

However, it may have a different function and biological

activity depending on the specific tumor type. For example,

Metwaly et al. [13] found that syndecan-1 increased signif-

icantly with increasing stage of hepatocellular carcinoma; in

breast carcinoma, syndecan-1 overexpression correlates

with poor prognosis and aggressive phenotype [14]; immu-

nohistochemical analysis showed high syndecan-1 protein

expression in high- grade, superficial, and deep invasive

bladder cancers as well as carcinoma in situ, but not in low-

grade and noninvasive phenotypes [15]. However, contra-

dictory findings have also been reported. For example, Wang

et al. [16] indicated that the decreased expression of synd-

ecan-1 mRNA in colorectal cancer was closely associated

with the degree of differentiation, the depth of infiltration,

lymph node metastasis, vessel metastasis, and TNM staging

of this tumor; Stepp et al. [17] detected the reduced expres-

sion of syndecan-1 in skin tumors, which is important both

early in the tumor development and tumor progression.

To our interests, Naganuma et al. [18] in 2004 detected the

high expression of syndecan-1 in malignant glioma cells.

Then, Watanabe et al. [19] in 2006 also found that the

malignant glioma cells expressed syndecan-1, and indicated

that nuclear factor-jB may participate in the up-regulation of

syndecan-1 at the transcriptional level. Based on these pre-

vious results, we hypothesized that syndecan-1 may play a

role in tumor progression of human gliomas. Therefore, the

aim of this study was to investigate the association between

syndecan-1 expression and clinicopathological features, and

to evaluate the potential prognostic value of syndecan-1

expression in patients with gliomas.

Materials and methods

Patients and tissue samples

This study was approved by the Research Ethics Com-

mittee of First Affiliated Hospital of Medical College,

Shantou University, P. R. China. Written informed consent

was obtained from all of the patients. All specimens were

handled and made anonymous according to the ethical and

legal standards.

A total of 116 glioma patients aged between 8 and

82 years (median = 45 years) between 2000 and 2010

were collected from Department of Neurosurgery, First

Affiliated Hospital of Medical College, Shantou Univer-

sity, P. R. China. All the patients underwent surgical tumor

resection, and diagnosis of glioma was confirmed by his-

tological examination, including 26 grade I, 30 grade II, 30

grade III tumors, and 30 grade IV tumors. None of the

patients had received chemotherapy or radiotherapy prior

to surgery. Formalin-fixed, paraffin-embedded sections of

tissue specimens were reviewed by our neuropathologists.

The clinicopathological features of all the patients were

indicated in Table 1. Normal brain specimens were

acquired from 15 patients undergoing surgery for epilepsy.

Five years follow-up was performed, and all patients had

complete follow-up until death. Overall survival time was

Table 1 Syndecan-1 expression in human glioma tissues with dif-

ferent clinical-pathological features

Clinicopathological

features

No. of

cases

Syndecan-1 P

positive

(n, %)

negative

(n, %)

WHO grade

I 26 16 (61.5) 10 (38.5) 0.01

II 30 20 (66.7) 10 (33.3)

III 30 26 (86.7) 4 (13.3)

IV 30 30 (100.0) 0 (0)

Age

\55 46 36 (78.3) 10 (21.7) NS

C55 70 56 (80.0) 14 (20.0)

Gender

Male 66 53 (80.3) 13 (19.7) NS

Female 50 39 (78.0) 11 (22.0)

KPS

\80 71 68 (95.8) 7 (4.2) 0.03

C80 45 28 (62.2) 17 (37.8)

8980 Mol Biol Rep (2012) 39:8979–8985

123

calculated from the date of the initial surgical operation to

death. All the patients who died from other diseases or

unexpected events were excluded from the evaluation.

Quantitative real-time PCR

Total RNA was extracted from frozen glioma and control

brain tissues using Trizol reagent (Invitrogen, Shanghai,

China) and reverse transcribed to cDNA using a Revert-

AidTM First Strand cDNA synthesis kit (Fermentas, Glen

Burnie, MD, USA) following the supplier’s instructions.

The primers 50-AGG ACG AAG GCA GCT ACT CCT-30

and 50-TTT GGT GGG CTT CTG GTA GG-30 were used to

amplify 70-bp transcripts of syndecan-1 and the primers 50-GGT GGC TTT TAG GAT GGC AAG-30 and 50-ACT GGA

ACG GTG AAG GTG ACA G-30 were used to amplify

161-bp transcripts of b-actin. All primers were synthesized

by Sangon Co. (Shanghai, China). The PCR profile con-

sisted of an initial melting step of 1 min at 94 �C, followed

by 38 cycles of 15 s at 94 �C, 15 s at 56 �C and 45 s at

72 �C, and a final elongation step of 10 min at 72 �C.

Reverse transcription PCR (RT-PCR) was performed at

least three times for each sample. Syndecan-1 mRNA levels

were compared to b-actin.

Western blot analysis

Total proteins were extracted from frozen glioma and control

brain tissues. From each sample, 50 lg of protein lysates was

subjected to sodium dodecyl sulfate–polyacrylamide gel

electrophoresis in 10 % acrylamide gel and transferred to

polyvinylidine difluoride membranes (Millipore Corpora-

tion, USA) at 350 mA for 2.5 h. The membrane was blocked

in 5 % nonfat milk and incubated with primary antibody

against syndecan-1 (clone 5F7, Novocastra, Newcastle, UK)

overnight at 4 �C, followed by incubation with horseradish

peroxidase-conjugated secondary antibody. Housekeeping

protein b-actin was used as a loading control. Positive

immunoreactive bands were quantified densitometrically

(Leica Q500IW image analysis system) and expressed as

ratio of syndecan-1 to b-actin in optical density units.

Immunohistochemistry assay

Immunohistochemical assay was performed using the con-

ventional immunoperoxidase technique according to the

protocol of the Department of Neurosurgery, First Affiliated

Hospital of Medical College, Shantou University, P. R. China.

Briefly, after being deparaffinized using a graded ethanol

series, the sections were blocked by soaking in 0.3 % hydro-

gen peroxide for 30 min. Then, the sections were processed in

10 mmol/L citrate buffer (pH 6.0) and heated to 121 �C in an

autoclave for 20 min for antigen retrieval. All incubations

with a mouse monoclonal antibody directed against syndecan-

1 (clone 5F7, Novocastra, Newcastle, UK) at 1:50 dilution

were carried out overnight at 4 �C. Later on, the specimens

were briefly washed in PBS and incubated at room tempera-

ture with the anti-moust antibody and avidin–biotin peroxi-

dase (Vector Laboratories Inc., Burlingame, CA, USA). After

rinsing in PBS, peroxidase reaction was visualized by incu-

bating the sections with diaminobenzidine tetrahydrochloride

in 0.05 mol/L Tris buffer (pH 7.6) containing 0.03 % hydro-

gen peroxide. Following these reactions, the sections were

counterstained with hematoxylin, dehydrated, and covers-

lipped. Normal brain tissues were used as control tissues and

non-immune IgG was also used as negative control antibody

for immunohistochemical staining.

Stained sections were observed under a microscope.

Immunostaining was scored by two independent experi-

enced pathologists, who were blinded to the clinicopatho-

logic parameters and clinical outcomes of the patients. An

immunoreactivity score system was applied as described

previously [20]. The percentage scoring of immunoreactive

tumor cells was as follows: 0 (0 %), 1 (1–10 %), 2

(11–50 %) and 3 ([50 %). (2) intensity of stain: colorless

scored 0; pallide-flavens scored 1; yellow scored 2; brown

scored 3. Multiply (1) and (2). Tumors with a multiplied

score exceeding 4 (i.e. tumors with a moderate or strong

staining intensity of [10 % of the tumor cells) were

deemed to be positive syndecan-1 expression; all other

scores were considered to be negative.

Statistical analysis

All computations were carried out using the software of SPSS

version13.0 for Windows (SPSS Inc, IL, USA). The results are

shown as mean ± standard deviation. Fisher’s exact test, Chi-

square, and two-sample t tests were used to compare clini-

copathological data. A Spearman’s analysis was carried out to

analyze the correlation between syndecan-1 mRNA and pro-

tein expression levels. In the analysis of glioma morbidity for

all patients, we used the Kaplan–Meier estimator and uni-

variate Cox regression analysis to assess the marginal effect of

each factor. The differences between groups were tested by

log-rank analyses. The joint effect of different factors was

assessed using multivariate Cox regression. Differences were

considered statistically significant when p was less than 0.05.

Results

Quantitative analysis of syndecan-1 gene expression

in gliomas

The expression of syndecan-1 gene was detected in 116

gliomas and 15 normal control brain tissue specimens

Mol Biol Rep (2012) 39:8979–8985 8981

123

normalized to b-actin. The increased expression of syndec-

an-1 gene was detected in glioma specimens compared to the

normal brain tissues, according to the glioma WHO grade

(Fig. 1a, b). The expression levels of syndecan-1 gene in

glioma tissues with high grade (grade III–IV; 1.9 ± 0.06)

and with low grade (I–II; 1.2 ± 0.03) were both significantly

higher than that in normal brain tissues (0.8 ± 0.01;

P \ 0.001 and 0.008, respectively). Additionally, the dif-

ference in syndecan-1 gene expression levels between high

grade (III–IV) and low grade (I–II) glioma tissue specimens

also had statistical significance (P = 0.02).

Quantitative analysis of syndecan-1 protein expression

in gliomas

As the results of Western blot analysis, the expression

levels of syndecan-1 protein were respectively 0.5 ± 0.02,

1.0 ± 0.03, 1.7 ± 0.08 for normal brain, glioma grade I–II

and glioma grade III–IV (normal brain versus I–II, P =

0.003; I–II versus III–IV, P \ 0.001; I–II versus III–IV,

P = 0.001) (Fig. 1c, d). There was a significant positive

correlation between the expression of syndecan-1 gene and

protein expression levels from the same glioma tissues

(rs = 0.88, P \ 0.001).

Immunostaining of syndecan-1 protein in glioma

tissues and survival analysis

Immunohistochemistry analysis was performed to detect

the expression of syndecan-1 protein in 15 normal brain

and 116 glioma tissue specimens. As shown in Fig. 2a,

positive staining for syndecan-1 was mainly observed on

the cell membranes and/or in the cytoplasm of the tumor

cells in glioma tissues. Syndecan-1 immunoreactivity was

not detected in the normal brain tissues (Fig. 2b). Among

the glioma tissue specimens, 96 (82.8 %) were positively

stained, and 24 (17.2 %) were negatively stained. Addi-

tionally, syndecan-1 expression was not significantly

affected by the gender and age (both P [ 0.05) of the

patients. In contrast, the syndecan-1 expression was the

closely correlated with WHO grade (Table 1; P = 0.01), as

well as Karnofsky performance Status (KPS) (Table 1;

P = 0.03).

In order to further determine the correlation of synd-

ecan-1 expression with clinical outcome in gliomas, we

reviewed clinical information of these syndecan-1-posi-

tive or -negative glioma patients. The median survival in

this cohort with resected glioma was 18 months. During

the follow-up period, 90 of the 116 glioma patients

(77.6 %) had died (9 from the syndecan-1-negative group

and 81 from the syndecan-1-positive group). We also

found a significant difference in patient overall survival

between the syndecan-1 negative expression and positive

expression groups (P = 0.006; Fig. 3). By multivariate

analysis, the syndecan-1 expression was a significant and

independent prognostic indicator for patients with glio-

mas besides age, WHO grade and KPS (P = 0.01).

The Cox proportional hazards model showed that synd-

ecan-1 over-expression was associated with poor overall

survival.

Fig. 1 Expression of syndecan-1 gene and protein in glioma and

normal brain tissues by RT-PCR and Western blot analysis, respec-

tively. a Expression level of syndecan-1 gene in different grades of

gliomas. b A graphical representation of the syndecan-1 gene

expression profiles in (a). c Expression level of syndecan-1 protein

in different grades of gliomas. d A graphical representation of the

syndecan-1 protein expression profiles in (c)

8982 Mol Biol Rep (2012) 39:8979–8985

123

Discussion

In this study, we investigated the expression of syndecan-1

at gene and protein levels in 116 cases of human gliomas

and compared its expression with tumor grade and survival

rates of patients. Our data demonstrated that syndecan-1

gene and protein were both increased in glioma tissues

compared to normal brain tissues. There was an increased

trend of both syndecan-1 protein level and mRNA level

from WHO grade I to WHO grade IV glioma, which

suggested that the transcriptional and translational activa-

tion of syndecan-1 might participate in the tumorigenesis

and progression of human gliomas.

Tumor metastasis and tumor invasion both are multistep

processes involving several crucial events: the loosening of

intercellular junctions, attachment of tumor cells to the

ECM, degradation of the ECM, migration of tumor cells

through the ECM, angiogenesis, detachment of tumor cells,

vascular permeation, the homing of tumor cells and traf-

ficking of cancer cells through blood vessels, extravasa-

tions, organ-specific homing, and growth [21]. A large

number of molecules participate in these processes. Syn-

decans act as coreceptors for growth factors and modulate

cell growth and differentiation [22]. Syndecan-1 as a

member of the syndecan family is mainly localized on the

cell plasma membrane of epithelial cell types, ranging from

staining over the entire cell surface to staining of only the

basolateral surface [23]. It functionally binds with extra-

cellular ligands mediated by heparan sulfate and it is an

important regulatory protein of cellular motility. Recent

studies have found that syndecan-1 expression is dysreg-

ulated in many cancers, such as breast cancer, ovary can-

cer, prostate cancer, gallbladder carcinoma, pancreas

carcinoma and colon cancer [9–16]. Interestingly, syndec-

an-1 plays different roles in different tumor types. Some

studies indicated that the down-regulation of cell-surface

syndecan-1 was associated with the malignant transfor-

mation of an epithelial cell, leading to decreased intercel-

lular cohesion, increased potential for tumor invasiveness

and metastatic spread. So the loss of syndecan-1 was cor-

related with high grade, advanced stage and poor prognosis

in some tumors, such as breast cancer [14], colorec-

tal adenoma/carcinoma [16], cutaneous squamous cell

Fig. 2 Immunohistochemical staining of syndecan-1 protein in tumor

cells of glioma tissues (a) and normal brain tissues (b) (Original

magnification 9400). Positive staining of syndecan-1 is seen on the

cell membrane of tumors cells in glioma tissues. Negative expression

of syndecan-1 was observed in normal brain tissues

Fig. 3 Postoperative survival curves for patterns of patients with

glioma and syndecan-1 expression. Kaplan–Meier postoperative

survival curve for patterns of patients with glioma and syndecan-1

expression shown that the patients with a negative syndecan-1

expression appeared to have a longer survival than those with a

positive syndecan-1 expression

Mol Biol Rep (2012) 39:8979–8985 8983

123

carcinoma [24], invasive cervical carcinoma [25], non-

small cell lung carcinoma [26], renal cell carcinoma [27]

and hepatocellular carcinoma [13]. However, other studies

conversely reported that the increased syndecan-1 expres-

sion was correlated with high grade and poor prognosis in

patients with some tumors, such as gallbladder carcinoma

[20], nasopharyngeal carcinoma [28], and papillary carci-

noma of the thyroid [9]. These findings suggest that

syndecan-1, like many other proteoglycans, modulates

several key processes of tumorigenesis, such as cancer cell

proliferation and apoptosis, angiogenesis, metastasis and

invasion. The present study is the first report to suggest a

correlation of syndecan-1 expression at gene and protein

levels with clinicopathological features and prognosis in

patients with gliomas. With the similar results with the

previous studies of Naganuma et al. [18] and Watanabe

et al. [19], we also detected the up-regulation of syndecan-

1 in glioma tissues compared with normal brain tissues.

Besides these findings, we further demonstrated the sur-

vival rate of patients with positive syndecan-1 staining was

lower than those without. Kaplan–Meier analysis of the

survival curves showed a significantly worse overall sur-

vival for patients whose tumors had high syndecan-1 lev-

els, indicating that high syndecan-1 protein level is a

marker of poor prognosis for patients with gliomas, which

was the same as the previous finding in gallbladder carci-

noma [20], nasopharyngeal carcinoma [28], and papillary

carcinoma of the thyroid [9]. Finally, multivariate analysis

showed syndecan-1 positive expression to be a marker of

worse outcome independent of the known clinical prog-

nostic indicators such as age, KPS and WHO grade.

In conclusion, our data provides convincing evidence

that the increased expression of syndecan-1 at gene and

protein levels is correlated with the advanced clinicopath-

ological features and poor outcome in patients with glio-

mas. Syndecan-1 might serve as a potential prognosis

predictor of this dismal tumor. A large sample size, a good

methodology and a detailed clinical follow-up in this study

make our results more reliable.

Conflict of interest None.

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