Experimental and Molecular Pathology 96 (2014) 200205

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Experimental and Molecular Pathology

journal homepage: www.elsevier.com/locate/yexmp

Signicance of NQO1 overexpression for prognostic evaluation of

gastric adenocarcinoma
Lijuan Lin a,b,1, Yunzhi Qin c,1, Tiefeng Jin a, Shuangping Liu a, Songnan Zhang d,
Xionghu Shen d,, Zhenhua Lin a,
a

Department of Pathology, Yanbian University Medical College, Yanji 133002, China

Department of Medical Imaging, College of Medicine, Eastern Liaoning University, Dandong 118003, China
Department of Anesthesiology, Yanbian University Hospital, Yanji 133000, China
d
Department of Oncology, Yanbian University Hospital, Yanji 133000, China
b
c

a r t i c l e

i n f o

Article history:
Received 19 November 2013
Available online 31 December 2013
Keywords:
NQO1
Gastric adenocarcinoma
Immunohistochemistry
Survival analysis

a b s t r a c t
NQO1 (NAD(P)H: quinone oxidoreductase, also known as DT-diaphorase) plays a prominent role in maintaining
cellular homeostasis. NQO1 is abnormally elevated in many solid cancer types, including those of the adrenal
gland, breast, colon, lung, ovary, and thyroid. However, little is known about the status of NQO1 in gastric adenocarcinoma (GAC). To investigate the clinicopathological signicance of NQO1 expression in GAC, and thus evaluate its role as a potential prognostic marker, 203 cases of primary GAC, 31 of gastric dysplasia, and 53 of adjacent
non-tumor tissues were selected for immunohistochemical staining of NQO1 protein. Correlations between
NQO1 overexpression and clinicopathological characteristics were evaluated by 2 test and Fisher's exact test,
while survival rates were calculated by KaplanMeier method. The relationship between prognostic factors
and patient survival was analyzed by Cox proportional hazards model.
Through these analyses it was found that the strongly positive rate of NQO1 protein in GAC was signicantly
higher than that in gastric dysplasia and adjacent non-tumor tissues. Analysis by qRT-PCR also conrmed that
NQO1 mRNA levels were increased in GAC compared with those detected in either adjacent non-tumor tissues
or normal gastric mucosa. Additionally, the NQO1 expression rate was positively correlated with tumor size,
serosal invasion, tumor stage, and both disease-free survival and 5-year survival rates. Further analysis showed
that although NQO1 was not an independent predictor of GAC, elevated expression of NQO1 could predict
lower disease-free survival and 5-year survival times in late-stage patients. In conclusion, NQO1 plays an important role in the progression of GAC, and might be a potential, but not an independent, poor prognostic biomarker
and therapeutic target of GAC.
2013 Elsevier Inc. All rights reserved.

Introduction
Gastric cancer is the fourth most common malignancy and the second leading cause of cancer deaths worldwide (Geng et al., 2013). The
development and progression of gastric cancer is a multistage process
which involves multiple molecular pathways and abnormal genetic
changes. Despite great advances in surgical and medical management
of the disease, the prognosis of gastric cancer has not signicantly improved. Therefore, identication of reliable criteria for predicting its recurrence and prognosis attracts widespread research interest.

Correspondence to: Z. Lin, Department of Pathology, Yanbian University Medical

College, No. 977, Gongyuan-Rd., Yanji 133002, China. Fax: +86 433 2435104.
Correspondence to: X. Shen, Department of Oncology, Yanbian University Hospital,
No. 1829, Juzi-St., Yanji 133000, China.
E-mail addresses: linlijuan3066@sina.com (L. Lin), 1559468491@qq.com (Y. Qin),
jintf@ybu.edu.cn (T. Jin), liushp@ybu.edu.cn (S. Liu), zhangsn@163.com (S. Zhang),
xim918@126.com (X. Shen), zhlin720@ybu.edu.cn (Z. Lin).
1
These authors contributed equally to this work.
0014-4800/$ see front matter 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.yexmp.2013.12.008

NAD(P)H: quinone oxidoreductase 1 (NQO1, also known as diphtheria toxin diaphorase (DT-diaphorase)), was discovered by Professor
Ernster in 1958 (Siegel et al., 2000) and is located on chromosome
16q22 (Zhuet al., 2013). NQO1 is a mainly cytosolic enzyme which uses
NADH or NADPH as substrates to directly reduce quinones to hydroquinones (Zhang et al., 2012). It is present in all tissue types with the exception of the liver (Siegel et al., 2000; Strassburget al., 2002) and is induced
along with a battery of defensive genes that provide protection against
different stresses to prevent organs from carcinogen-induced tumorigenesis. Because there is an increased incidence of disease and xenobioticinduced toxicity in individuals carrying a polymorphism in NQO1, it has
been suggested that it has a role in chemoprotection.
Paradoxically, in spite of this cell protector status, NQO1 expression has been found to be increased during malignant transformation
in some tumor types including that of the adrenal gland, breast, colon,
lung, ovary, and thyroid (Garate et al., 2010; Lewis et al., 2005; LynCook et al., 2006), and has also been detected following the induction
of cell cycle progression and proliferation of melanoma cells (Garate et
al., 2010). To date, the role of NQO1 in cancer progression remains

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201

Fig. 1. Immunohistochemical staining of NQO1 in gastric lesions. A: Gastric mucosa. B: Atypical cells of gastric dysplasia. C: Gastric adenocarcinoma (GAC) with lymph node metastasis. D:
GAC without lymph node metastasis. E: Invasive cancer loci. F: Metastatic cancer cells in blood vessels (arrows). Magnication is 100 in A and 200 in BF.

controversial. Notably, its role in GAC progression has not yet been reported. This study aimed to determine the NQO1 protein expression status in GAC, dysplasia, and adjacent non-tumor tissues, and thereby
determine its potential as a prognostic biomarker and therapeutic target
in this disease.
Materials and methods
Clinical samples
Two hundred and three GAC cases were selected randomly from the
Department of Pathology Tumor Tissue Bank, Yanbian University Medical College. These specimens were collected from patients undergoing
surgical treatment between 2004 and 2008. The cohort included 135
males and 68 females, ranging from 29 to 72 years old, with a mean
age of 49.7. All cases were conrmed as GAC by pathological examination. Tumor stage was determined according to the 7th edition of the
American Joint Committee on Cancer (AJCC). Of the 203 samples, 101
cases were stages IIIa while 102 cases were stages IIbIIIc. Tumor
stage was closely correlated with prognosis. In addition, 80 cases were
dened as well-differentiated while 123 cases were poor to mildly differentiated. Fifty-three cases of normal gastric mucosa tissues obtained
from the periphery of malignant GAC tissue and 31 cases of gastric
dysplasia were also included in the study. None of the patients received
radio-chemotherapy before surgery. The 203 patients with GAC had
been followed for ve years or until death. At the end of the followup, 105 patients remained alive.
Fresh samples were also collected and included 12 cases of GAC, 8
cases of adjacent non-tumor tissue and 8 cases of normal gastric mucosa. These were used for RNA extraction and qRT-PCR analysis of NQO1
mRNA.

Immunohistochemistry
To eliminate endogenous peroxidase activity, 4 m thick tissue sections were deparafnized, rehydrated and incubated with 3% H2O2 in
methanol for 15 min at room temperature (RT). The antigen was retrieved by placing the slides in 0.01 M sodium citrate buffer (pH 6.0)
at 95 C for 20 min. The slides were then incubated with NQO1 antibody
(1:50, sc-32793, Santa Cruz Biotechnology, Inc. USA) at 4 C overnight.
After incubation with biotinylated secondary antibody at RT for
30 min, the slides were incubated with streptavidinperoxidase complex at RT for 30 min. Immunostaining was developed using 3,3-diaminobenzidine, and Mayer's hematoxylin was used for counterstaining.
We used tonsil sections as the positive control and mouse IgG as an
isotope control. Some positive tissue sections were also processed with
omission of the primary antibody (mouse anti-NQO1) as an additional
negative control.
All specimens were blind examined by two pathologists. In case
of discrepancies, a nal score was established by reassessment on a
double-headed microscope. The immunostaining for NQO1 was semiquantitatively scored as (negative) no or less than 5% positive
cells; + 525% positive cells; ++ 2650% positive cells; and +++
more than 50% positive cells. Only cytoplasmic staining was considered
positive. For statistical analysis, the strongly positive group represents
the combined scores of ++ and +++ positive cells.
RNA extraction and quantitative real-time polymerase chain reaction
(qRT-PCR)
Total RNA of fresh tissues was extracted using Trizol reagent
(Invitrogen, Carlsbad, CA). First-strand cDNA was synthesized using
PrimeScript reverse transcriptase (TaKaRa Bio, Dalian, China) and oligo

Table 1
NQO1 protein expression in gastric lesions.
Diagnosis

Gastric adenocarcinoma
Gastric dysplasia
Adjacent non-tumor tissues

No. of cases

203
31
53

NQO1 protein expression

++

+++

49
14
32

29
5
7

54
6
9

71
6
5

Positive rate

Strongly positive rate

75.86%
54.84%
39.62%

61.58%
38.71%
26.42%

Statistical analyses were performed using Pearson Chi-square test. Gastric adenocarcinoma compared with Gastric dysplasia, P b 0.05; Gastric adenocarcinoma compared with Adjacent
non-tumor tissues, P b 0.01.

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L. Lin et al. / Experimental and Molecular Pathology 96 (2014) 200205

(dT) following the manufacturer's instructions. To examine expression,

real-time PCR was performed with a Bio-Rad sequence detection system
using double-stranded DNA-specic SYBR Premix Ex TaqTM II Kit
(TaKaRa Bio) according to the manufacturer's instructions. Doublestranded DNA specic expression was tested by the comparative Ct method using 2-Ct. NQO1 primers were as follows: 5-GGCAGAAGAGCACT
GATCGTA-3, and 5-TGATGGGATTGAAGTTCATGGC-3. GAPDH was used
for an internal control: 5-GGTCTCCTCTGACTTCAACA-3 and 5-ATACCA
GGAAATGAGCTTGA-3. All assays were performed in triplicate at least
three times.
Statistical analysis
Analyses were performed using SPSS 17.0. Correlations between
NQO1 expression and clinicopathological characteristics were evaluated by the Chi-square ( 2) and Fisher's exact tests. The survival
rates after tumor removal were calculated by the KaplanMeier
method, and differences in survival curves were analyzed by the
Log-rank test. Univariate and multivariate survival analysis were
performed on all the characteristics measured by the Cox proportional hazard regression model. P b 0.05 was considered statistically
signicant.
Results
Expression of NQO1 in GAC
The positive and strongly positive expression rates of NQO1 protein
were 75.86% (154/203) and 61.58% (125/203) in GAC, respectively,
which was signicantly higher than those in either gastric dysplasia tissues (54.84% and 38.71%, both P b 0.05) or adjacent non-tumor tissues
39.62% and 26.42%, both P b 0.01. However, no signicant difference
between gastric dysplasia and adjacent non-tumor tissues was found
(P N 0.05) (Fig. 1 and Table 1).
Analysis by qRT-PCR also conrmed that NQO1 expression increased
at the mRNA level in GAC when compared with that in either adjacent
non-tumor tissue or normal gastric mucosa (Fig. 2).
Clinicopathologic and prognostic signicance of NQO1 expression in GAC
To elucidate the role of NQO1 in GAC progression, we analyzed the
correlation between NQO1 expression and clinicopathological features
of GAC. As shown in Table 2, elevated NQO1 expression was closely
associated with tumor size (P = 0.014), serosal invasion (P = 0.018),

Table 2
Univariate analysis of NQO1 expression and various risk factors in 203 GAC patients.
Variables

Age
b50
50
Gender
Male
Female
Tumor size
5 cm
N5 cm
Differentiation
Well
Moderate and Poor
Clinical stage
IIIa
IIbIIIc
LN metastasis
Positive
Negative
Serosal invasion
Yes
No

NQO1 expression (%)

/+

++/+++

32 (40.00%)
46 (37.40%)

48 (60.00%)
77 (62.60%)

54 (40.00%)
24 (35.29%)

81 (60.00%)
44 (64.71%)

51 (45.95)
27 (29.35%)

60 (54.05%)
65 (70.65%)

35 (43.75%)
43 (34.96%)

45 (56.25%)
80 (65.04%)

47 (46.53%)
31 (30.39%)

54 (53.47%)
71 (69.61%)

43 (35.25%)
35 (43.21%)

79 (64.75%)
46 (56.79%)

41 (32.03%)
37 (49.33%)

87 (67.97%)
38 (50.67%)

HR (95% CI)

P value

1.116 (0.6261.988)

0.710

1.222 (0.6672.238)

0.516

2.046 (1.1413.668)

0.016

1.447 (0.8132.576)

0.209

1.993 (1.1213.543)

0.018

0.715 (0.4021.272)

0.254

0.484 (0.2700.869)

0.015

P b 0.05.
P b 0.01.

and clinical stage (P = 0.015), but did not correlate with age, gender,
differentiation, or lymph node metastasis (all P N 0.05). Moreover,
GAC patients with elevated NQO1 expression had both a shorter
disease-free survival rate (Log-rank = 11.960, P = 0.001) and
ve-year survival rate (Log-rank = 12.571, P b 0.001) than those
with low NQO1 expression, as determined by KaplanMeier analysis
(Fig. 3).
Cox proportional hazard regression model analysis for independent
prognostic factors in GAC
Univariate analysis was performed for all of the variables by Cox
analysis. It was found that GAC patients with elevated NQO1 expression
had a signicantly lower overall survival rate than those with low NQO1
expressing tumors (HR: 1.391, 95% CI: 1.0481.848, P = 0.022). Tumor
size, differentiation, lymph node metastasis, serosal invasion, and stage,
were also associated with reduced overall survival rate. However,
further multivariate analysis showed that only tumor stage proved to
be an independent prognostic factor for survival in GAC (HR: 1.807,
95% CI: 1.3532.413, P = 0.000). NQO1 expression, in contrast, did
not emerge as a signicant independent prognostic factor in GAC (HR:
1.196, 95% CI: 0.8901.607, P = 0.236) (Table 3).
NQO1 combined with tumor stage predicts prognosis in GAC
Further survival analysis showed that patients with late-stage
GAC concomitant with elevated NQO1 expression had both poorer
disease-free survival and ve-year survival rates than those with
low NQO1 expression (Fig. 4CD), indicating that NQO1 might be
a useful prognostic marker for late-stage GAC. Of note, although
there was no statistical connection between patients with highand low expression of NQO1 in early-stage GACs, there was still
a tendency for survival in patients with high NQO1 expression to
be comparatively shorter than those with NQO1 low-expression
(Fig. 4AB).

Fig. 2. qRT-PCR analysis of NQO1 mRNA. Normal gastric mucosa (normal), adjacent nontumor tissues (non-tumor) and GAC tissues were collected and subjected to qRT-PCR analysis of NQO1 mRNA levels. Data represents the mean of individual samples tested in triplicate relative to that of the normal control SD. **P b 0.01.

Discussion
NQO1 provides protection for cells against free radical damage, oxidative stress, and accumulation of toxic substances (Garate et al., 2010;

L. Lin et al. / Experimental and Molecular Pathology 96 (2014) 200205

203

Fig. 3. KaplanMeier analysis of GAC patient survival rates in relation to NQO1 protein expression. Disease-free survival (A) and overall survival rates (ve-year survival) (B) of patients
with elevated (green, n = 125) and low (blue, n = 78) NQO1 expression.

Zhu et al., 2013) by catalyzing two-electron reduction of quinones and

nitrogen oxides (Riley et al., 1992) and also by the direct conversion of
quinones to hydroquinones. Varying NQO1 genotypes encode different
enzymes which may affect enzyme activities. Indeed, the homozygous TT genotype lacks NQO1 activity and thus might result in reduced detoxication of exogenous carcinogens. Therefore, many
studies have tested the hypothesis that the C609T polymorphism
might be linked to the risk of cancers, such as cervical, lung, bladder
and colorectal. Niwa and colleagues (Niwa et al., 2005) studied the
effect of NQO1 genotypes on cervical carcinogenesis in relation to
smoking behaviors and showed that the TT genotype was a risk
factor only for cervical squamous cell carcinoma while the C allele
was over-expressed in invasive cervical cancer and cervical
intraepithelial neoplasia. Fagerholm's study on breast cancer patients showed that NQO1 may predict the outcome of patients with
overabundant FANCD2 protein through its potential modication
of prognostic DNA repair markers (Fagerholm et al., 2013). Moreover, Li et al. (2011) highlights that NQO1 is more than a biomarker,
but also an exploitable, tumor-selective target, whose expression is not
cell-cycle regulated, nor affected by alterations in common tumor

Table 3
Univariate and multivariate survival analyses (Cox regression model) of various factors in
203 GAC patients.
Factors

SE

Wald

HR (95% CI)

P value

Univariate
Age
Sex
Tumor size
Differentiation
Stage
LN
SI
NQO1

0.052
0.057
0.339
0.349
0.623
0.307
0.308
0.331

0.144
0.147
0.141
0.144
0.142
0.143
0.145
0.216

0.131
0.148
5.770
5.846
19.358
4.577
4.457
5.215

1.054 (0.7941.398)
1.058 (0.7941.411)
1.404 (1.0641.851)
1.417 (1.0681.880)
1.864 (1.4132.460)
1.359 (1.0261.800)
1.361 (1.0221.811)
1.392 (1.0481.848)

0.717
0.700
0.016
0.016
0.000
0.032
0.035
0.022

Multivariate
Tumor size
Differentiation
Stage
LN
SI
NQO1

0.149
0.270
0.591
0.239
0.288
0.179

0.147
0.149
0.148
0.150
0.151
0.151

1.033
3.294
16.035
2.553
3.643
1.406

1.161 (0.8711.549)
1.310 (0.9791.753)
1.807 (1.3532.413)
1.270 (0.9471.704)
1.334 (0.9921.792)
1.196 (0.8901.607)

0.309
0.070
0.000

SI: serosal invasion, LN: lymph node metastasis.

P b 0.05.
P b 0.01.

0.110
0.056
0.236

suppressors, such as p53 or Rb. Beyond these reports, the function of

NQO1 in malignancies remains controversial.
Recently, it was reported that NQO1 protein and mRNA expression levels are abnormally elevated within many solid tumors.
Awadallah et al. (2008) reported that NQO1 is upregulated in pancreatic ductal adenocarcinoma (PDAC), and that combining NQO1
expression with cellular morphology assessment minimizes the
risk of false positive diagnosis. Lyn-Cook et al. (2006) also considered
that NQO1 may represent a useful biomarker for pancreatic cancer,
while Liang's research (Liang et al., 2013) showed that expression
of NQO1 tends to be higher (3060%) in lung cancers compared
with normal lung tissue, but is not signicantly different from that
in peri-cancer tissues. In the present study, we found that NQO1 protein expression was frequently upregulated in GAC compared with
that in either gastric dysplasia or adjacent non-tumor tissues. The
strongly positive rate of NQO1 protein was 61.58% (125/203) in
GAC cases, which was signicantly greater than that in either gastric
dysplasia or adjacent non-tumor gastric mucosa. Analysis by qRTPCR also revealed increased NQO1 at the mRNA level in GAC compared with that in adjacent non-tumor tissues and normal gastric
mucosa. These results indicate that NQO1 is involved in the progression of GAC, and that NQO1 protein level might be a diagnostic indicator of this disease.
Furthermore, accumulating studies have demonstrated that elevated NQO1 expression is associated with the poor prognosis of
malignancies. Mikami et al. (1998) demonstrated that the expression and enzyme activity of NQO1 is not only upregulated in
colon cancer cell lines and colorectal tumors, but is also signicantly greater in tumors with nodal metastases than those without.
Awadallah et al. (2008) also suggests that NQO1 overexpression
is a clinically useful prognostic adjunct for detection of PDAC, independent of tumor stage. Here we found that NQO1 overexpression
was closely related with increased tumor size, serosal invasion, and
late-stage tumors, raising the possibility that NQO1 expression
participates in the tumorigenesis and malignant progression of
GAC. Consequently, NQO1 might be useful as a poor prognostic biomarker of GAC.
In regard to survival, we found that GAC patients with high NQO1
expression had both lower disease-free survival (P = 0.001) and overall survival rates (P b 0.001) than those with low NQO1 expression.
Univariate survival analysis indicated that tumor size, differentiation,
clinical stage, lymph node metastasis, serosal invasion and NQO1
expression are all signicantly related with disease-free and overall

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L. Lin et al. / Experimental and Molecular Pathology 96 (2014) 200205

Fig. 4. KaplanMeier analysis of survival rates in patients with high or low NQO1 with early- or late-stage GAC. Disease-free survival (A) and overall survival rates (ve-year survival) (B)
were assessed in patients with early-stage GAC concomitant with either high (green line, n = 54) or low (blue, n = 47) NQO1 expression. Disease-free survival (C) and overall survival
rates (D) were also assessed in patients with late-stage GAC concomitant with high (green, n = 71) or low (blue, n = 31) NQO1 expression.

survival rates of GAC patients (P b 0.05). However, through multivariate survival analysis, only clinical stage emerged as a signicant independent hazard factor for overall survival in GAC. Notably, late-stage
GAC concomitant with high NQO1 expression was correlated with
shorter disease-free survival and ve-year survival times than those
with low NQO1 expression (P = 0.039 and P = 0.035, respectively).
A similar tendency was observed in patients with early-stage GAC.
Therefore, although NQO1 expression in GAC was not found to be an independent risk factor for patients' survival in the present study, it was
revealed that NQO1 serves as a useful biomarker for prognosis of GAC,
especially for late-stage disease.
In conclusion, NQO1 plays an important role in the tumorigenesis
and progression of GAC, and is a potential effective predictor for its
poor prognosis, especially in late stage disease. Consequently, determination of NQO1 expression in GAC may aid the selection of appropriate
therapies.
Conict of interest statement
The authors declare that there are no conicts of interest.
Author's contributions
LL, QY, and JT participated in the study conception, design, case
selection and experiments. ZS, PL and SX carried out the data

collection. LL, LS, and LZ performed the data analysis and writing
of the manuscript. All the authors read and approved the nal
manuscript.
Acknowledgments
This study was supported by grants from the National Natural
Science Foundation of China (61371067 & 31301065), and the Projects of Research & Innovation of Jilin Youth Leader and Team
(20130521017JH).
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