Hindawi Publishing Corporation

Stem Cells International

Volume 2015, Article ID 247892, 8 pages
http://dx.doi.org/10.1155/2015/247892

Research Article
Osteopontin Overexpression Induced Tumor Progression and
Chemoresistance to Oxaliplatin through Induction of Stem-Like
Properties in Human Colorectal Cancer
Lui Ng,1 Timothy Wan,1 Ariel Chow,1,2 Deepak Iyer,1 Johnny Man,1 Guanghua Chen,1
Thomas Chung-Cheung Yau,1,2 Oswens Lo,1 Chi-Chung Foo,1 Jensen Tung-Chung Poon,1
Ronnie Tung-Ping Poon,1,2 Roberta Pang,1,2 and Wai-Lun Law1
1

Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong

Correspondence should be addressed to Roberta Pang; robertap@hku.hk

Received 9 March 2015; Revised 7 May 2015; Accepted 12 May 2015
Academic Editor: Yupo Ma
Copyright 2015 Lui Ng et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Colorectal cancer (CRC) is one of the most common and fatal malignancies worldwide. The poor prognosis of colorectal cancer
patients is due to development of chemoresistance and cancer metastasis. Recently osteopontin (OPN) has been associated with
stem-like properties in colorectal cancer. This study further examined the clinicopathological significance of OPN in CRC and its
effect on chemoresistance and transcription of stem cell markers. We examined the transcription level of OPN in 84 CRC patients
and correlated the expression with their clinicopathological parameters. The associations of OPN overexpression with transcription
of stem cell markers and response to chemotherapy in DLD1-OPN overexpressing clones and CRC patients were also investigated.
Our results showed that OPN was significantly overexpressed in CRC, and its overexpression correlated with tumor stage and
poor prognosis. Overexpression of CRC induced OCT4 and SOX2 expression in vitro and correlated with SOX2 overexpression
in CRC patients. In addition, DLD1-OPN overexpressing cells showed enhanced ability to survive upon oxaliplatin treatment, and
OPN expression was higher in CRC patients who were resistant to oxaliplatin-involved chemotherapy treatment. Thus, CRC cells
overexpressing OPN demonstrated stem-like properties and OPN inhibition is a potential therapeutic approach to combat CRC
progression and chemoresistance.

1. Introduction
Colorectal cancer (CRC) is the third most common malignancy around the world [1]. Annually, over 1.2 million people
develop CRC globally, with more than 600,000 patients dying
from the disease in 2008 [2]. Both the incidence and the death
rates from CRC are increasing rapidly in Asian countries
[3]. Incidence and mortality rates for CRC have declined
as a result of improved tests that allow early detection of
the cancer, when it can be more easily treated by surgery
and chemotherapy along with radiotherapy [4]. Despite
those advances in clinical treatment, the overall prognosis
of CRC patients is still unsatisfactory due to development
of chemoresistance and cancer metastasis. Therefore, it is
important to understand how CRC cells acquired the ability

to survive upon chemotherapy and metastasize to distant

regions, in order to develop new therapeutic target and
approach to improve the prognosis and survival rates of CRC
patients.
Osteopontin (OPN), a member of the Small IntegrinBinding Ligand N-linked Glycoprotein (SIBLING) family,
is expressed in normal mineralized tissues, epithelial cells
of some metabolically active ducts, and several neoplastic
tissues [5]. OPN is involved in most aspects of tumor biology.
Through its diverse reported functions related to proliferation, survival, angiogenesis, escape from host defense, tumor
development, invasion, and metastasis, OPN covers multiple
hallmarks of cancer [6]. Indeed, OPN expression significantly
correlates with tumor stage in various cancer types.

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In colorectal cancer, OPN downregulation suppressed
in vitro proliferation and in vivo tumorigenicity and also
suppressed in vitro invasion and migration capacity [7]. We
also showed in our previous study that stable overexpression
of OPN in DLD1 cells significantly induced the protein
expression and secretory level of OPN, and the migration
ability of DLD1 cells [8]. In addition, OPN overexpression is
associated with activation of the epithelial to mesenchymal
pathway through induction of Twist and Snail and downregulation of E-cadherin.
Recently, OPN has been associated with cancer stem
cell nature in colorectal cancer. OPN secreted from tumor
associated cells increased CD44v6 expression in colorectal
cancer stem cells by activating the Wnt/-catenin pathway,
which promotes migration and metastasis [9]. This study
will further investigate the in vitro effect of OPN overexpression on growth response to chemotherapy. In addition,
a recent study demonstrated that OPN silencing suppressed
transcriptions of key stemness transcription factors SOX2,
Oct3/4, and Nanog in vitro and glioblastoma stem-like cell
character and tumorigenicity in vivo [10]. This study will
also study the effect of OPN overexpression on stemness of
CRC cells, by investigating its correlation with transcription
of stem cell markers.

2. Materials and Methods

2.1. Patients and Specimens. The human sample collection
protocol has been approved by the Institutional Review
Board (IRB) of the University of Hong Kong, and all clinical
investigation has been conducted according to the principles
expressed in the Declaration of Helsinki. Informed written
consent has been obtained from the participants. Tissue
samples were obtained from 84 patients, immediately frozen
in liquid nitrogen and kept at 80 C until analysis. Clinicopathological data were obtained from the patient database of
our hospital.
2.2. Cell-Lines, Tissue Culture, Transfections, and Reagents.
Construction of stable OPN overexpressing or vector control
DLD1 cells was described previously [8]. DLD1-OPN stable
clones and vector control were maintained in DMEM with
10% fetal bovine serum and antibiotics (Invitrogen, Carlsbad,
CA), 5% CO2 at 37 C.
2.3. RNA Extraction. Total RNA was extracted using Trizol
reagent and Purelink RNA Mini Kit (Life Technologies,
Carlsbad, CA) according to the manufacturers instructions.
The RNA yield and quality were analyzed by NanoDrop 2000
(Thermo Scientific).
2.4. cDNA Synthesis and Quantitative Real-Time Polymerase
Chain Reaction. 500 ng total RNA was reversely transcribed
with PrimeScript 1st strand cDNA Synthesis Kit (Takara,
Tokyo, Japan) in accordance with the instructions of the
manufacturer. Real-time PCR was performed in a final
volume of 15 L containing 1.5 L RT transcript, 0.2 M

Stem Cells International

of each primer, 1x ROX reference dye, and 7.5 L of FastStart Universal SYBR Green Master (ROX) (Roche Diagnostics, Switzerland, Basel). A no RT transcript control
was included for each gene to ensure the signal was truly
driven by target gene amplification. The primer sequences
were as follows: OPN-Forward Primer: 5 -TGGGGGTCACTGCAATTAG-3, OPN-Reverse Primer: 5 -TGGGGCTAGGAGATTCTG-3 ; GAPDH-Forward Primer: 5 GTCTCCTCTGACTTCAACAGCG-3 , GAPDH-Reverse
Primer: 5 -ACCACCCTGTTGCTGTAGCCAA-3 ; OCT4Forward Primer: 5 -GTGGAGGAAGCTGACAACAA-3,
OCT4-Reverse Primer: 5 -GCCGGTTACAGAACCACACT-3 ; SOX2-Forward Primer: 5 -GACAGTTACGCGCACATGAA-3, SOX2-Reverse Primer: 5 -TAGGTCTGCGAGCTGGTCAT-3 ; Nanog-Forward Primer: 5 -GTGATTTGTGGGCCTGAAGA-3, Nanog-Reverse Primer: 5 ACACAGCTGGGTGGAAGAGA-3 . Real-time PCR was
carried out using the ABI 7900HT Fast Real-Time PCR
System (Applied Biosystems, Foster, CA) at 95 C for 10 min,
followed by 40 cycles at 95 C for 15 sec and at 56 C for 1 min.
Each assay was done in triplicate, the average was calculated,
and the expression level of target mRNA was normalized by
the expression of GAPDH (delta Ct); that is, the higher the
delta Ct, the lower the target gene expression.
2.5. Cell Viability Assay. Same number of cells were seeded
on 96-well plate for 24 hours and then subjected to treatment
of chemotherapeutic drugs 5 M oxaliplatin or 50 M 5Fluorouracil (5FU). The cell viability at 72 h after drug
treatment was determined using the 3-[4,5-dimethylthiazol2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) (Invitrogen).
2.6. Immunohistochemical Staining. Immunohistochemical
staining was performed as described previously [11]. Sections were incubated with the primary antibodies antiOPN (OriGene Technologies, Rockville, MD) and anti-SOX2
(Cell Signaling Technology, Danvers, MA) at 1 : 100 dilutions
overnight at 4 C in a moist chamber. A scoring system
related to the extent and intensity of immunostaining of
enterocytes was used. The intensity of positive staining was
scored as 0, negative; 1, weak; 2, moderate; 3, strong by two
independent observers. The extent of positive staining was
scored as 1 (<10%), 2 (1050%), and 3 (>50%). The final score
was determined by multiplying the intensity score and extent
score, yielding a range from 0 to 12.
2.7. Statistical Analysis. The association of OPN level with
stem cell markers was tested with Pearson correlation. Students -test was applied to compare difference between two
groups. Survival rates were analyzed with log-rank test. All
of these statistical analyses were performed with SigmaPlot
10.0 (Systat Software Inc., San Jose, CA, USA). Statistical
significance was set at 0.05.

3. Results
3.1. OPN Was Overexpressed in CRC. We first compared the
expression of OPN in CRC and the paired nontumor mucosa
of 84 CRC patients. The OPN expression was determined by

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3
Table 1: Clinicopathological correlation of OPN overexpression in CRC ( = 84).

Clinicopathological features
Age
Gender
Tumor size
Histological grade
Lymph node metastasis
Tumor AJCC stage
Distant metastasis

Category

Number of cases

<65
65
Male
Female
<5 cm
5 cm
Well/moderate
Poor/undifferentiated
Absent
Present
I to II
III to IV
Absent
Present

34
50
59
25
49
35
75
9
37
47
31
53
64
20

qRT-PCR and expressed as fold change to the adjacent nontumor tissue using the 2Ct method. Our results showed that
the mean expression of OPN in CRC was significantly higher
than that in the nontumor tissue (7.4-fold, < 0.001).
3.2. OPN Overexpression Correlated with Advanced Tumor
Stage. We next examined the clinicopathological significance
of OPN overexpression (expressed as Ct (Ct of CRC, Ct
of nontumor tissue), that is, lower Ct value represented
higher OPN overexpression in CRC) in 84 CRC patients
(Table 1). OPN overexpression was not associated with age,
gender, and tumor size, but there was a trend of higher OPN
overexpression in patients with lymph node metastasis ( =
0.057) and distant metastasis ( = 0.088). In addition, when
we divided the patients into lower stage (no lymph node
and distant metastasis) and higher stage (presence of lymph
node and/or distant metastasis), patients of higher CRC stage
showed significantly higher OPN overexpression ( = 0.014).
OPN overexpression was also significantly correlated with
tumor stage ( = 0.252, = 0.0195; Figure 1(b)). Moreover,
our results showed that OPN overexpression correlated with
the grade of CRC. Poorly differentiated CRC that tend
to be more aggressive showed higher OPN overexpression
when compared with well or moderately differentiated CRC
( = 0.02). These results suggested that OPN overexpression
correlated with disease progression of CRC.
3.3. OPN Overexpression Correlated with Poor Prognosis.
The associations of OPN overexpression with disease-free
survival (DFS) and overall survival (OS) were investigated.
We divided the 84 CRC patients into 2 groups according to
the OPN overexpression status of their CRC. For patients
whose OPN overexpression was below the median level of
the 84 patients (Ct > 0.617), they were regarded as low
OPN overexpression. On the other hand, for those whose
OPN overexpression was above the median level (Ct
0.617), they were regarded as high OPN overexpression.
We first compared the DFS rates between the two groups of

OPN overexpression
(Ct) (mean SEM)
0.613 0.475
0.767 0.371
0.542 0.335
1.089 0.581
0.824 0.412
0.537 0.400
0.599 0.309
3.024 1.472
0.081 0.422
1.196 0.390
0.219 0.474
1.245 0.352
0.427 0.338
1.594 0.537

value
0.798
0.394
0.630
0.020
0.057
0.014
0.088

patients. Though high OPN overexpression patients appeared

to have a worse DFS than that of weak overexpression group,
the difference was not statistically significant ( = 0.274;
Figure 1(c)). On the other hand, patients with low OPN overexpression have a significantly better OS rate than patients
with high OPN overexpression ( = 0.023; Figure 1(d)).
These results suggested that OPN overexpression correlated
with poor prognosis in CRC patients.
3.4. Correlation of OPN Overexpression with Stem Cell Marker
Levels. To investigate the effect of OPN overexpression
on transcription of stem cell markers, we determined the
transcription level of OCT4, SOX2, and Nanog [12] in two
DLD1-OPN overexpressing cells DLD1-OPN #1 and #3 and
the vector control DLD1-Vc [8] by qRT-PCR. As shown in
Figure 2(a), OPN transcript expression of DLD1-OPN #1 and
3 was significantly higher than that of vector control. The
expressions of OCT4 and SOX2 were also significantly higher
in DLD1-OPN stable clones when compared with the vector
control (Figures 2(b) and 2(c)), suggesting that overexpression of OPN induces the transcription of OCT4 and SOX2.
In addition, the induction effect of OPN overexpression on
SOX2 was higher than that on OCT4. On the other hand,
though Nanog expression appeared higher in DLD1-OPN
stable clones than in vector control, the difference was not
statistically significant (Figure 2(d)).
We next examined the correlation of OPN with OCT4,
SOX2, and Nanog in the CRC patients. Overexpression of
OPN in CRC positively correlated with SOX2 overexpression
( = 0.231, = 0.0451; Figure 3(a)), suggesting that tumor
cells with high OPN expression possess cancer stem cell-like
properties. On the other hand, OPN overexpression in CRC
did not correlate with Nanog overexpression ( = 0.009,
= 0.940), which is in accordance with the result obtained
in our cell-line experiment. Furthermore, overexpression of
OPN in CRC did not correlate with OCT4 overexpression
( = 0.171, = 0.173), which is not in accordance with
our cell-line data.

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14
12

p < 0.001

Tumor stage

OPN expression
(fold-difference to nontumor tissue)

10
8

6
R = 0.252, p = 0.0195

6
2

4
2

0
15

0
Nontumor tissue

10

CRC

0
5
5
OPN overexpression (Ct)

(a)

1.0

10

(b)

1.0

Low OPN overexpression

Low OPN overexpression

0.8
p = 0.274

0.6

High OPN overexpression

0.4

Overall survival

Disease-free survival

0.8

p = 0.023

0.6

0.4
High OPN overexpression
0.2

0.2

0.0

0.0
0

10

20

30
40
Time (months)

50

60

70

(c)

10

20

30
40
Time (months)

50

60

70

(d)

Figure 1: (a) Relative transcript expression of OPN (expressed as fold change to the adjacent nontumor tissue using the 2Ct method) of
84 patients; correlation of OPN overexpression (expressed as Ct (Ct of CRC Ct of nontumor)) with (b) tumor stage, (c) disease-free
survival, and (d) overall survival of CRC patients.

We further investigated the correlation of OPN and SOX2

protein expression in 11 CRC patients using immunohistochemistry. There was a positive correlation between OPN and
SOX2 expression in the CRC specimen tested ( = 0.871,
< 0.001; Figures 3(b) and 3(c)).
3.5. OPN Overexpression Induces Chemoresistance to Oxaliplatin Treatment. OPN overexpression was associated with
chemoresistance in small-cell lung cancer, breast cancer,
and glioma [1315]; yet its role in CRC chemoresistance
has not been demonstrated. To examine the effect of OPN
overexpression on chemoresistance of CRC cells, we treated
the DLD1-OPN stable cells and vector control with oxaliplatin
and 5-FU which are common chemodrugs to treat CRC
patients and determined the relative number of viable cells

after 72 hours by MTT assay. The effect on CRC cell viability

was expressed as percentage of viable cells when compared
with vehicle treated cells. As shown in Figure 2(e), our results
showed that following 5 M oxaliplatin treatment, the percentage of viable vector control cells (43.0%) was significantly
lower than that of DLD1-OPN #1 (56.7%, = 0.018) and
DLD1-OPN #3 (53.3%, = 0.048). On the other hand, OPN
overexpression did not enhance the chemoresistance of DLD1
cells to 50 M 5FU treatment (Figure 2(f)).
We also compared the OPN overexpression in CRC
patients who received chemotherapy. 55 patients with
detailed clinical information after administration of chemotherapy treatment were included in this comparison. Among
these patients, 29 of them were sensitive to the treatment
(tumor responsive to chemotherapy and no recurrence

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500

300

200

100

p = 0.032

400

p = 0.009

Relative OCT4 expression

(fold to vector control)

Relative OPN expression

(fold to vector control)

p < 0.001

4
3

p = 0.002

2
1

0
Vector control

DLD1-OPN #1

DLD1-OPN #3

Vector control

(a)

DLD1-OPN #3

(b)

16

40

14

30

20

10

p = 0.012

Relative Nanog expression

(fold to vector control)

p = 0.016
Relative SOX2 expression
(fold to vector control)

DLD1-OPN #1

p = 0.096

12
10
8
6
4

p = 0.522

2
0

0
Vector control

DLD1-OPN #1

Vector control

DLD1-OPN #3

(c)

DLD1-OPN #3

(d)

80
p = 0.018

60

p = 0.048

40

20

Relative cell number

(% of control treatment)

80

Relative cell number

(% of control treatment)

DLD1-OPN #1

60
p = 0.329

p = 0.482

DLD1-OPN #1

DLD1-OPN #3

40

20

0
Vector control

DLD1-OPN #1

DLD1-OPN #3

Vector control

(e)

(f)

Figure 2: Relative overexpression (expressed as Ct (Ct of CRC Ct of nontumor)) of (a) OPN, (b) OCT4, (c) SOX2, and (d) Nanog in
DLD1-OPN stable clones #1 and #3 and the vector control; the relative number of viable cells (expressed as percentage of viable cells when
compared with vehicle treated cells) after 72-hour treatment of (e) 5 M oxaliplatin and (f) 50 M 5FU.

within at least 1 year) while 26 of them were resistant (tumor

not responsive to chemotherapy or recurrence within 1 year).
The chemoresistance patients showed higher OPN overexpression when compared with the chemosensitive patients
(2.427 versus 0.385, = 0.013).

4. Discussion
Previously, involvement of OPN in most aspects of tumor
biology has been reported. Through its diverse reported
functions related to proliferation, survival, angiogenesis,

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16

10

14
12
SOX2 expression

SOX2 overexpression

0
5
R = 0.231, p = 0.0451

10
R = 0.871, p < 0.001

8
6
4

10

2
15
15

0
10

0
5
OPN overexpression

10

(a)

6
8
OPN expression

10

12

14

(b)

767N

621T

621N

SOX2

OPN

767T

(c)

Figure 3: (a) Correlation of OPN mRNA overexpression with SOX2 mRNA overexpression in CRC patients. (b) Correlation of OPN protein
expression with SOX2 protein expression in CRC tissues of 11 patients. (c) Representative images showing correlation of OPN and SOX2
protein expression in CRC tissues (621T: OPN high/SOX2 high; 767T: OPN low/SOX2 low). Negative/weak staining of OPN and SOX2 were
detected in most adjacent normal tissues (N).

escape from host defense, tumor development, invasion, and

metastasis, OPN covers multiple hallmarks of cancer [6].
Indeed, OPN expression significantly correlates with tumor
stage in various cancer types.
In colorectal cancer, OPN downregulation suppressed
in vitro proliferation and in vivo tumorigenicity and also
suppressed in vitro invasion and migration capacity [7]. We
also showed in our previous study that stable overexpression
of OPN in DLD1 cells significantly induced the protein
expression and secretory level of OPN, and the migration
ability of DLD1 cells [8]. In this study, we further examined the clinicopathological significance of OPN expression
in CRC and its association with stem-like property and
chemoresistance.
We showed that OPN overexpression in CRC correlated
with higher grade, tumor stage, and survival of CRC patients,
indicating that OPN overexpression was associated with poor
prognosis. Stem-like nature of CRC cells has been suggested

to associate with tumor progression, metastasis, and poor

survival [16, 17], which is in accordance with the clinicopathological characteristics observed in our patients with high
OPN overexpression. In addition, OPN has been associated
with cancer stem cell in colorectal cancer. OPN secreted
from tumor associated cells increased CD44v6 expression in
colorectal cancer stem cells by activating the Wnt/-catenin
pathway, which promotes migration and metastasis [9]. This
study further investigated the effects of OPN overexpression
on transcriptions of key stemness transcription factors SOX2,
OCT4, and Nanog, in which transcription repression by OPN
silencing has been demonstrated in stem-like glioblastoma
cells in vivo [10]. The expression of OCT4 and SOX2 was
significantly higher in DLD1-OPN stable clones #1 and #3,
when compared with the vector control. In addition, their
expression in DLD1-OPN #1 which expressed higher level
of OPN was higher than that in DLD1-OPN #3, further
indicating that OPN overexpression induced the expression

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of OCT4 and SOX2, which are associated with the stemlike properties of CRC cells [18]. We next examined the
correlation of overexpression of OPN with that of OCT4
and SOX2 in CRC patients. In accordance with our in vitro
data, OPN overexpression in CRC significantly correlated
with SOX2 overexpression. Interestingly, no correlation was
observed between OPN and OCT4. As our in vitro data
showed that DLD1-OPN #1 and #3 demonstrated 22.8-fold
and 5.7-fold induction of SOX2, respectively, whereas only
3.6-fold and 2.2-fold induction of OCT4 was detected in
DLD1-OPN #1 and #3, respectively, we suggest that the
correlation of OPN with SOX2 is stronger than that with
OCT4 and thus only such correlation was observed in our
patient cohort. Nonetheless, as SOX2 was known to be a stem
cell factor in CRC which enhanced CRC cell proliferation,
migration, and invasion [19, 20], our results indicated that
OPN overexpression induced stem-like properties of CRC
cells through overexpression of SOX2.
This study also demonstrated that DLD1-OPN stable
clones showed improved survival rate upon oxaliplatin treatment. In addition, DLD1-OPN #1 which showed higher OPN
expression than DLD1-OPN #3 was more resistant to the
effect of oxaliplatin, suggesting that OPN overexpression
indeed regulated such chemoresistance. Previously, OPN
downregulation was reported to enhance in vitro radiosensitivity of CRC cells [7]. This study further strengthened
the unfavourable effects of OPN overexpression on treatment of CRC patients. To our knowledge, this is the first
report showing OPN overexpression induced oxaliplatinchemoresistance. We believed that such drug-resistant effect
was associated with the stem cell-like properties in OPN overexpressing cells, as oxaliplatin-resistant CRC cells showed
higher levels of stem cell markers SOX2 and OCT4 [21,
22]. We also investigated the effect of OPN overexpression
on response of 55 CRC patients to chemotherapy involving
oxaliplatin. The mean OPN overexpression of the 26 resistant
patients was higher than that of the 29 sensitive patients,
suggesting that OPN expression in CRC patients could be
a biomarker for predicting the response to chemotherapy
involving oxaliplatin. Also, the effect of OPN inhibition on
oxaliplatin-based chemotherapy of CRC patients warrants
further investigation.
Recently, CD44v6 has been reported as a colorectal CSC
marker required for the metastatic potential of CSCs, and
OPN, HGF, and SDF-1 increased CD44v6 expression in
CSCs [9]. OPN has been suggested to activate the pathway
associated with HGF and SDF-1. Ligation of OPN to integrins
leads to activation of HGF receptor (Met) and is known to
increase the sensitivity of mammary epithelial cell lines to
the cell migration promotion effect of HGF/Met [23]. OPN
potentiated tumor growth via interaction with mesenchymal
stromal cell to upregulate expression of CCL5 and cancerassociated fibroblast markers including SDF-1 [24]. These
results showed that OPN overexpression in CRC possibly
enhanced the stemness properties of cancer cells through
induction of CD44v6 expression, as well as through activation or upregulation of HGF and SDF-1, which are also
upregulators of CD44v6.

7
This study, in combination with the results from other
OPN studies (reviewed in [25]), suggested that OPN is
a therapeutic target for cancer. Silencing of OPN using
RNAi technology, blocking OPN activity using specific antibodies, and small-molecule inhibitors might repress tumor
progression and metastasis and enhance the response to
chemotherapy in CRC, and possibly in other types of cancer.

5. Conclusions
This study demonstrated that OPN overexpression correlated
with tumor progression and poor prognosis in CRC patients,
possibly by inducing stem-like property of CRC cells as
reflected by overexpression of SOX2, which is associated with
ability to metastasize and survive upon oxaliplatin-involved
chemotherapy treatment.

Conflict of Interests
No conflict of interests was disclosed by the authors.

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