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Gene Section
Review
SDC1 (syndecan 1)
Anurag Purushothaman, Ralph D Sanderson
Dept. of Pathology, University of Alabama at Birmingham, 814 SHEL, 1530 Third Ave. S., Birmingham,
AL 35294, USA (AP, RDS)
Published in Atlas Database: March 2008
Online updated version: http://AtlasGeneticsOncology.org/Genes/SDC1ID42223ch2p24.html
DOI: 10.4267/2042/44386
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Variant 2: exons-5; transcript length-3217 bp and
translation length -310 residues.
Other names: CD138; SDC; SYND1; Syndecan
HGNC (Hugo): SDC1
Location: 2p24.1
Local order: Human syndecan1 gene is localized to
2p23-24, just centromeric to the N-myc gene at
2p24.1.
Note: Syndecan 1, a cell surface heparan sulfate
proteo-glycan, is one of the four members of the
syndecan family.
Pseudogene
None
Protein
Description
310 amino acids; 32477 Da; charge -19.5; iso-electric
point 4.2618.
The core protein contains 3 domains, an ectodomain
(extracellular domain), transmembrane domain and
cytoplasmic domain. The ectodomain contains a
cleavable amino terminal single peptide and the
glycosaminoglycan attachment sites. There are 3 highly
conserved serine-glycine sites for heparan sulfate
attachment (amino acids 37,45 and 47) near the N
terminal of the core protein and 2 highly conserved
serine-glycine sites for chondro-itin sulfate attachment
( amino acids 210 and 220), adjacent to the cell
membrane. Shedding of the ectodomain occurs via
protease sensitive sites near the plasma membrane. The
transmembrane domain, which is highly conserved
among the syndecan family members, contains an
unusual motif of glycine/alanine that aligns on one face
of the domain in the outer membrane leaflet. The noncatalytic COOH-terminal, cytoplasmic domain, which
is relatively short (30 amino acids) contains 2 highly
conserved regions (C1 and C2) which are identical in
each of the 4 syndecan family members (the exception
being a conservative substitution of arginine for lysine
in syndecan 2). These flank a central variable region
(V) that is distant for each family member.
DNA/RNA
Genomic structure of the two alternative transcript variants of
SDC1. Black boxes indicate exons and red boxes indicate
untranslated exons.
Description
The SDC1 gene contains 9 exons and spans 24, 6366
bases (start 20,264,039 bp from pter to end 20,288,675)
oriented at the minus strand.
Transcription
While several transcript variants may exist for this
gene, the full-length natures of only two have been
described to date. These two represent the major
variants of this gene and encode the same protein.
Variant 1 (NM_001006946) represents the longer
transcript and variant 2 (NM_002997) differs in the 5'
UTR compared to variant 1.
Variant 1: exons-6; transcript length-3309 bp and
translation length -310 residues.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1)
57
SDC1 (syndecan 1)
Purushothaman A, Sanderson RD
Schematic representation of the core protein structure of SDC1. C1 and C2 represent highly conserved regions and V represents the
central variable region. Lines at amino acids 37, 45 and 47 represents heparan sulfate chain attachment sites and lines at amino acids
210 and 220 represents chondroitin sulfate chain attachment sites.
The sequence for variable domain (V) for SDC1 is
SLEEPKQANGGAYQKPTKQE. The cytoplasmic
domain of SDC1 is required for linking the molecule to
the cytoskeleton and this interaction is dependent on a
tyrosine residue that is conserved among all known
syndecan family sequences. The cytoplasmic V region
plays critical role in lamellipodial spreading, actin
bundling and cell migration.
5 hydrophobic amino acids, AVAAV (amino acids
222-226), which are critical for the SDC1 mediated
inhibition of tumor cell invasion.
Homology
Belongs to the syndecan family; four members,
syndecan- 1, syndecan-2, syndecan-3 and syndecan-4,
have been identified in mammalians. SDC1 orthologs
are found in mouse, rat, dog, chimpanzee, guinea pig,
Chinese hamster, Hedgehog, cat, Pika, Platypus,
Bushbaby, Tree Shrew, and chicken. The extracellular
domains of human and mouse SDC1 show 70%
sequence identity while the trans-membrane domain
and cytoplasmic domain show 96 % and 100% identity
respectively (see MapViewer).
Expression
SDC1 is expressed predominantly on epithelial cells
but is also found on distinct stages of differentiation of
normal lymphoid cells (pre-B), mesenchymal cells
during development and in mature plasma cells.
Localisation
Mutations
Membrane; Single-pass type I membrane protein.
Function
Note
No mutations in the SDC1 gene have been reported.
The
syndecan-1
proteoglycan
regulates
cell
proliferation, cell migration, cell signaling, cytoskeletal
organization and mediates both cell-cell and cellextracellular matrix interactions. Additionally, via its
heparan sulfate chains, it binds a wide range of
bioactive molecules (e.g., growth factors, chemokines)
that regulate cell behaviors important in normal and
pathological processes. For example, it can function as
trans HIV receptors via binding of HIV-1 gp120 to the
syndecan heparan sulfate chains and also serves as a
primary receptor for natural HPV infection of
keratinocytes. SDC1 is required for Wnt-1-induced
mammary tumorigenesis and can function as either
tumor suppressor or tumor promoter depending on
tumor type and specific location of the proteoglycan
(either cell surface or shed into the microenvironment).
Core proteins also have functions independent of the
heparan sulfate chains. The cytoplasmic domains can
transmit signals and they also bind to anchoring
molecules including PDZ family members. The
extracellular domains bear the attached heparan sulfate
chains but also interact with, and regulate, other cell
adhesion molecules and cell surface receptors
independent of their heparan sulfate chains. It was
recently demonstrated that a domain within the
syndecan-1 core protein is required for activation of
alphaV/beta3 and alphaV/beta5 integrins and
mutational analysis of SDC1 has identified a stretch of
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1)
Implicated in
Multiple Myelomas
Note
Syndecan-1 (CD138) is the dominant heparan sulfate
proteoglycan expressed on the surface of myeloma
cells both in bone marrow and in peripheral blood, and
is used as a standard marker by many labs for
identification and purification of myeloma cells. On
normal cells, syndecan-1 is not expressed on mature B
lymphocytes but becomes present at the onset of
plasma cell differentiation.
Disease
Myeloma resides predominantly within the bone and is
marked by fatigue, intractable bone pain, renal failure
and recurrent infections. These effects result from high
tumor
burden
with
accompanying
cytokine
dysregulation, osteolytic bone disease and from the
deposition in some patients of high levels of
immunoglobulin light chain. Cell surface SDC1
mediates adhesion of myeloma cells to collagen,
inhibits invasion through collagen gels and also can
mediate myeloma cell-cell adhesion. In contrast, shed
syndecan-1 actively promotes myeloma tumor growth
and metastasis.
58
SDC1 (syndecan 1)
Purushothaman A, Sanderson RD
Prognosis
Shedding of syndecan-1 from the myeloma cell surface
occurs actively via proteolytic sheddases and a high
level of syndecan-1 in the serum is an independent
predictor of poor prognosis in myeloma. Patients with
high serum SDC1 had a median survival of 20 months,
whereas those with a low serum SDC1 had a median
survival of 44 months.
Disease
Carcinoma of the pancreas is the 4th leading cause of
cancer death in Western countries, with a very short
patient survival after diagnosis. Pancreatic cancers
over-express a variety of mitogenic growth factors and
their receptors and they exhibit tumor-suppressor gene
mutations such as p53, p16 and Smad4 and protooncogene mutations such as k-ras.
Prognosis
Patients with stromal syndecan-1-positive pancrea-tic
cancer had a worse outcome than patients with stromal
syndecan-1 negative tumors. Stromal expression of
syndecan-1 seems to be an indepen-dent prognostic
factor in pancreatic cancer.
Haematological malignancies
Note
SDC1 (CD138) is detectable on B-cell chronic
lymphocytic
leukemia
(B-CLL)
cells,
acute
lymphoblastic leukemia (ALL) cells and acute
myeloblastic leukemia (AML) cells.
Disease
The serum levels of syndecan-1 were elevated in
patients with B-cell chronic lymphocytic leukemia
(CLL) and Hodgkin disease (HL).
Prognosis
Serum CD138 level is higher in early stage B-CLL
patients than in healthy controls, correlates negatively
with peripheral blood lymphocyte count, and is higher
in patients with more indolent disease course. Serum
CD138 levels increase in early stage B-CLL patients
and may have a positive prognostic value as to the
dynamics of the disease. The serum levels of syndecan1 were elevated in patients with HL but did not
correlate with markers of tumor burden and prognosis,
including serum interleukin-10 and soluble CD30.
Gastric cancer
Note
Stromal syndecan-1 expression correlates with deep
tumor penetration and larger tumor size. Positive
stromal syndecan-1 immunoreactivity correlated with
decreased epithelial syndecan-1 expression.
Disease
Risk factors for gastric cancer include: Helicobacter
pylori gastric infection, advanced age, male gender,
diet including dry salted foods, atrophic gastritis,
pernicious anemia, cigarette smoking, Menetrier's
disease, and familial polyposis. The prognosis of
patients with gastric cancer is related to tumor extent
and includes both nodal involvement and direct tumor
extension beyond the gastric wall.
Prognosis
High expression of syndecan-1 in the stroma in gastric
carcinoma is a tumor characteristic associa-ted with a
poor prognosis independent of tumor size. Patients with
low epithelial syndecan-1 expression in cancer cells
had worse overall survival than patients with strong
epithelial syndecan-1 staining. Stromal syndecan-1positive patients had a worse outcome than patients
with syndecan-1 negative stroma.
Breast tumors
Note
Syndecan-1 is expressed at high levels in a significant
percentage of breast carcinomas and is related to an
aggressive phenotype and poor prognosis. High
syndecan-1 expression contributes to the identification
of a patient population at particularly high risk of
relapse and death.
Disease
High syndecan-1 expression in breast tumors is
associated with an aggressive phenotype characterized
by larger tumor size, higher tumor grade, higher mitotic
count, negative steroid status, and over expression of cerbB-2 and p53.
Prognosis
In breast cancer, increased expression of SDC1
correlates with an unfavorable prognosis and poor
response to chemotherapy.
Prostrate cancer
Note
Expression of syndecan-1 is associated with established
features of biologically aggressive prostate cancer
including high PSA levels and lymph node metastases.
Disease
Prostate cancer is the most common noncutaneous
malignancy affecting males in the USA. The disease
course is variable and about a third of patients
eventually fail treatment, as evidenced by a detectable
and rising PSA levels.
Prognosis
Patients with features of aggressive progression were
more likely to exhibit increased syndecan-1 expression
compared with those with features of non aggressive
progression.
Pancreatic cancer
Note
Syndecan-1 is upregulated in the stroma of pancreatic
cancer. Pancreatic cancer tissues express significantly
higher levels of syndecan-1 mRNA and protein. SDC1
over expression is an early event in pancreatic
carcinogenesis.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1)
59
SDC1 (syndecan 1)
Purushothaman A, Sanderson RD
membrane proteoglycans.
25;265(12):6884-9
Endometrial Cancer
Note
Stromal syndecan-1 expression is elevated in highgrade endometrial cancer.
Disease
Endometrial cancer is the most common disease among
gynecological malignancies and remains a major health
concern worldwide.
Prognosis
Loss of epithelial syndecan-1 expression and induction
of stromal syndecan-1 expression are associated with
reduced survival outcomes in patients with endometrial
cancer. Stromal syndecan-1 expression serves as an
indicator of poor prognosis in patients with endometrial
cancer.
Biol
Chem.
1990
Apr
Lories V, Cassiman JJ, Van den Berghe H, David G.
Differential expression of cell surface heparan sulfate
proteoglycans in human mammary epithelial cells and lung
fibroblasts. J Biol Chem. 1992 Jan 15;267(2):1116-22
Carey DJ, Bendt KM, Stahl RC. The cytoplasmic domain of
syndecan-1 is required for cytoskeleton association but not
detergent insolubility. Identification of essential cytoplasmic
domain residues. J Biol Chem. 1996 Jun 21;271(25):15253-60
Kaukonen J, Alanen-Kurki L, Jalkanen M, Palotie A. The
mapping and visual ordering of the human syndecan-1 and Nmyc genes near the telomeric region of chromosome 2p. Hum
Genet. 1997 Mar;99(3):295-7
Bernfield M, Götte M, Park PW, Reizes O, Fitzgerald ML,
Lincecum J, Zako M. Functions of cell surface heparan sulfate
proteoglycans. Annu Rev Biochem. 1999;68:729-77
Ovary carcinoma
Dhodapkar MV, Sanderson RD. Syndecan-1 (CD 138) in
myeloma and lymphoid malignancies: a multifunctional
regulator of cell behavior within the tumor microenvironment.
Leuk Lymphoma. 1999 Jun;34(1-2):35-43
Note
Syndecan-1 is present in the epithelial cells, cancer
cells, and stromal cells of benign, borderline, and
malignant ovarian tumor sections. Stromal syndecan-1
expression is observed in the most invasive areas of
ovarian cancer.
Disease
Epithelial carcinoma of the ovary is one of the most
common gynecologic malignancies. The most
important risk factor for ovarian cancer is a family
history of a first-degree relative (mother, daughter, or
sister) with the disease.
Prognosis
Stromal syndecan-1 expression is associated with
decreased survival in patients with ovarian carcinoma.
Alexander CM, Reichsman F, Hinkes MT, Lincecum J, Becker
KA, Cumberledge S, Bernfield M. Syndecan-1 is required for
Wnt-1-induced mammary tumorigenesis in mice. Nat Genet.
2000 Jul;25(3):329-32
Sanderson RD. Heparan sulfate proteoglycans in invasion and
metastasis. Semin Cell Dev Biol. 2001 Apr;12(2):89-98
Yang Y, Yaccoby S, Liu W, Langford JK, Pumphrey CY, Theus
A, Epstein J, Sanderson RD. Soluble syndecan-1 promotes
growth of myeloma tumors in vivo. Blood. 2002 Jul
15;100(2):610-7
Anisfeld AM, Kast-Woelbern HR, Meyer ME, Jones SA, Zhang
Y, Williams KJ, Willson T, Edwards PA. Syndecan-1
expression is regulated in an isoform-specific manner by the
farnesoid-X
receptor.
J
Biol
Chem.
2003
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30;278(22):20420-8
Lung cancers
Barbareschi M, Maisonneuve P, Aldovini D, Cangi MG,
Pecciarini L, Angelo Mauri F, Veronese S, Caffo O, Lucenti A,
Palma PD, Galligioni E, Doglioni C. High syndecan-1
expression in breast carcinoma is related to an aggressive
phenotype and to poorer prognosis. Cancer. 2003 Aug
1;98(3):474-83
Note
Serum syndecan-1 is a powerful prognostic factor in
lung cancer. Lung cancer patients have high serum
syndecan 1. High levels of circulating syndecan-1 also
in part reflect the presence of a large tumor mass and
are associated with advanced cancer.
Disease
Lung cancers are neuroendocrine lung tumors (small
cell lung carcinomas, carcinoids, large cell
neuroendocrine carcinomas) or non neuroendocrine
lung tumors (squamous carcinomas, adenocarcino-mas,
large cell carcinomas).
Prognosis
High serum syndecan-1 levels at diagnosis are
associated with an advanced stage and poor outcome in
lung cancer.
Beauvais DM, Rapraeger AC. Syndecan-1-mediated cell
spreading requires signaling by alphavbeta3 integrins in
human breast carcinoma cells. Exp Cell Res. 2003 Jun
10;286(2):219-32
Shafti-Keramat S, Handisurya A, Kriehuber E, Meneguzzi G,
Slupetzky K, Kirnbauer R. Different heparan sulfate
proteoglycans serve as cellular receptors for human
papillomaviruses. J Virol. 2003 Dec;77(24):13125-35
Maeda T, Alexander CM, Friedl A. Induction of syndecan-1
expression in stromal fibroblasts promotes proliferation of
human breast cancer cells. Cancer Res. 2004 Jan
15;64(2):612-21
Mennerich D, Vogel A, Klaman I, Dahl E, Lichtner RB,
Rosenthal A, Pohlenz HD, Thierauch KH, Sommer A. Shift of
syndecan-1 expression from epithelial to stromal cells during
progression of solid tumours. Eur J Cancer. 2004
Jun;40(9):1373-82
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This article should be referenced as such:
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1)
Purushothaman A, Sanderson RD. SDC1 (syndecan 1). Atlas
Genet Cytogenet Oncol Haematol. 2009; 13(1):57-61.
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