PTP4A3 (PRL-3) expression correlate with lymphatic metastases in gastric cancer

Department of General Pathomorphology, Medical University of Białystok, Białystok, Poland.
Folia Histochemica et Cytobiologica (Impact Factor: 1.36). 12/2010; 48(4):632-6. DOI: 10.2478/v10042-010-0070-7
Source: PubMed
ABSTRACT
Many studies have proved that protein tyrosine phosphatase type IVAmember 3 (PTP4A3, PRL-3) plays a major role in the metastasis of gastric cancer, especially to local lymph nodes. The objective of the current study was to assess the expression of PTP4A3 in gastric cancer in correlation with chosen anatomoclinical parameters and patients' survival. Atotal of 71 patients with gastric carcinomas were divided according to Lauren's, Goseki's, Bormann's and Kubo's classifications. The level of PTP4A3 was determined immunohistochemically using a mouse monoclonal anti-PTP4A3 antibody (clone 3B6, anti-human PTP4A3, Attogen Biomedical Research, USA). A statistically significant correlation was observed between PTP4A3 and Kubo's classifications (p=0.0454) and on the verge of statistical significance with Lauren's classification (p=0.0503). The expression of the protein was associated more with the poorly-differentiated mucoid carcinoma and diffused-type carcinoma (58% of cases). We demonstrated a statistically significant correlation between local lymph node involvement and positive expression of PTP4A3 in the primary tumour (p=0.0000). The current study seems to prove that PTP4A3 may have a significant impact on the lymphatic spread of gastric carcinoma. The protein expression is also significantly associated with gastric carcinomas having a worse prognosis, although patients' survival rate showed lack of correlation with PTP4A3 expression.

Full-text

Available from: Anna Pryczynicz, Oct 29, 2015
©Polish Histochemical et Cytochemical Society
Folia Histochem Cytobiol. 2010:48(4): 632 (632-636)
Doi: 10.2478/v10042-010-0070-7
Introduction
The incidence of gastric carcinoma in Poland is very
high. According to the National Cancer Registry, it is
the sixth most common malignancy among men and
the eighth among women [1]. The stage of the disease
is the most important prognostic factor. Gastric can-
cers frequently metastasize to the nearest lymph nodes,
involving retroperitoneal and left supraclavicular
lymph nodes as well as distant organs. The ability of
cancer cells to disseminate from the primary tumour to
lymph nodes and to the nearest and distant tissues and
organs is a fundamental feature of malignancies and
the major cause of therapeutic failures. Metastasis for-
mation is a complex and multistage process involving
proteolysis, mobility and migration of cells, prolifera-
tion and angiogenesis. Cancer cells, released from the
primary tumour, invade the surrounding tissues, pene-
trate into lymphatic or blood vessels, then migrate
through the vascular walls to the adjacent tissues,
where they eventually settle, proliferate, induce angio-
genesis, forming metastatic foci. Early detection of
metastases greatly improves the patients' prognosis.
Recently, it has been found that the protein formerly
known as phosphatase of regenerating liver-3 (PRL-3)
new named protein tyrosine phosphatase type IV A
member 3 (PTP4A3) could be used as a marker for
detecting early stage metastases [2].
The PTP family comprises of a large group of
enzymes involved in one of the most important cellu-
lar reaction, i.e. dephosphorylation of tyrosine
residues, affecting activation or inactivation of
enzymes. PTPs regulate many cellular processes, both
physiological and pathological, including cell growth,
differentiation, cycle or neoplastic transformation.
Non-classic representatives of this family include
three closely related proteins phosphatases (PTP4A1-
PTP4A3) with a unique COOH terminal group. All
FOLIA HISTOCHEMICA
ET CYTOBIOLOGICA
Vol. 48, No. 4, 2010
pp. 632-636
PTP4A3 (PRL-3) expression correlate with lymphatic
metastases in gastric cancer
Anna Pryczynicz
1
, Katarzyna Guziñska-Ustymowicz
1
, Xiao-Jia Chang
2
,
Joanna Kiœluk
1
, Andrzej Kemona
1
1
Department of General Pathomorphology, Medical University of Bia³ystok, Bia³ystok, Poland
2
Attogen Biomedical Research, 100 Barber Avenue, Worcester, MA 01606, USA
Abstract: Many studies have proved that protein tyrosine phosphatase type IV A member 3 (PTP4A3, PRL-3) plays a major
role in the metastasis of gastric cancer, especially to local lymph nodes. The objective of the current study was to assess the
expression of PTP4A3 in gastric cancer in correlation with chosen anatomoclinical parameters and patients' survival. A total
of 71 patients with gastric carcinomas were divided according to Lauren's, Goseki's, Bormann's and Kubo's classifications.
The level of PTP4A3 was determined immunohistochemically using a mouse monoclonal anti-PTP4A3 antibody (clone
3B6, anti-human PTP4A3, Attogen Biomedical Research, USA). A statistically significant correlation was observed
between PTP4A3 and Kubo's classifications (p=0.0454) and on the verge of statistical significance with Lauren's classifi-
cation (p=0.0503). The expression of the protein was associated more with the poorly-differentiated mucoid carcinoma and
diffused-type carcinoma (58% of cases). We demonstrated a statistically significant correlation between local lymph node
involvement and positive expression of PTP4A3 in the primary tumour (p=0.0000). The current study seems to prove that
PTP4A3 may have a significant impact on the lymphatic spread of gastric carcinoma. The protein expression is also signif-
icantly associated with gastric carcinomas having a worse prognosis, although patients' survival rate showed lack of corre-
lation with PTP4A3 expression.
Key words: gastric cancer, protein tyrosine phosphatase type IVA member 3, PTP4A3, PRL 3
Corresponding: Katarzyna Guziñska-Ustymowicz, MD,
Department of General Pathomorphology, Medical University
of Bia³ystok, ul. Waszyngtona 13, 15-269 Bialystok, Poland.
Tel: +48 85 7485942, Fax: +48-85-7485996,
e-mail: kasia.guzinska@gmail.com
Page 1
these proteins share at least 75% of their amino acid
sequences. PTP4A1 is localized mainly in the brain
and muscles, PTP4A2 is expressed in the skeletal mus-
cles and PTP4A3 predominantly in the myocardium
and skeletal muscles [2]. The PTP4A3 molecule, also
known as PTP4A3, possesses an enzyme active site
labelled with the CX
5
R signature, where Cys104 is an
enzymatic nucleophil and Arg110 binds the phosphate
groups on phosphotyrosine [3]. The PTP4A3 molecule
contains a C-terminal consensus sequence for prenyla-
tion and can be found in membranes and intercellular
structures when it is prenylated, whereas in the nucle-
us when it is non-prenylated. The PTP proteins in
which the C-terminal group has undergone mutation or
is lacking are located in the cytoplasm and/or cell
nucleus [4]. The role of PTP4A3 has not been fully
elucidated. Matter et al. [5] have suggested that
PTP4A3 can play a role in the regulation of intercellu-
lar calcium transmitters induced by angiotensin II. Wu
et al. [6] have identified PTP4A3 in cell membrane
components during mitosis or metaphase. This loca-
tion may suggest that PTP4A3 is engaged in the regu-
lation of cell cycle. This protein also plays a significant
part in the induction of angiogenesis through recruit-
ment of endothelial cells from the circulating blood
and is involved in the formation of microcirculation
[7]. However, abnormal regulation of tyrosine phos-
phorylation and dephosphorylation may result in can-
cer. Saha et al. [8] were the first to show the relation-
ship between PTP4A3 expression and liver metastases
of colorectal carcinoma. The protein overexpression
was also observed in cancer of the ovaries [9], breasts
[10] and stomach [11].
The aim of the current study was to assess the
expression of PTP4A3 in gastric carcinoma in correla-
tion with chosen anatomoclinical parameters.
Materials and methods
The study was conducted on a group of 71 patients treated surgi-
cally for gastric carcinoma in the Department of Surgery. Sections,
4 μm thick, were cut from paraffin blocks and stained with hema-
toxylin-eosin (H+E). The routine histopathological assessment
covered tumour location, histological type, malignancy grade (G),
stage (pTN) and the presence of metastases to local lymph nodes.
Gastric carcinomas were divided according to Lauren's [12], Gose-
ki's [13], Bormann's [14] and Kubo's [15] classifications.
Immunohistochemical analysis. Formalin-fixed and paraffin-
embedded tissue specimens were cut on a microtome into 4 μm sec-
tions. The sections were deparaffinized in xylene and hydrated in
alcohol. To visualize the antigen, the sections were heated in a
microwave oven for 15 min in a citrate buffer (pH 6.0). They were
incubated with 0.5% hydrogen peroxide solution in methanol in
order to block endogenous peroxidase. Incubation was performed
with mouse monoclonal antibody against human PTP4A3 (mono-
clonal antibody 3B6, Attogen Biomedical Research, USA – anti-
PTP4A3 antibody clone 3B6 has been previously described by Peng
et al., 2004 [16] over the night at 4°C. The reaction was carried out
using biotinylated anti-mouse antibody and streptavidin-conjugated
with horseradish peroxidase (LSAB2, DAKO, Poland). A colour
reaction for peroxidase was developed with chromogene
diaminobenzidine (DAKO, Poland). Protein expression was deter-
mined using a semiquantitative method and assessed as positive
(reaction visible in >5% of tumour cells) or negative (lack of reac-
tion, or reaction present in <5% of cells). Positive reactions were
assessed in at least 500 cancer cells in each tissue specimen under a
light microscope (×400).
Statistical analysis. Statistical analysis was conducted using Fish-
er's test and χ
2
. Log-rank test according to Kaplan-Meier survival
analysis approach was employed to compare the overall survival
rates of patients. A p-value <0.05 was considered statistically sig-
nificant.
Results
The study group consisted of 71 patients with gastric
carcinoma. Twenty-two patients had metastases to
lymph nodes, including 9 with metastases to group N1
lymph nodes (nodes 1-6), 12 to group N2 (nodes 5-11)
and one to group N3 (nodes 12-14). Positive cytoplas-
mic PTP4A3 expression in main mass of tumor has
been presented in Figure 2. Statistical analysis
revealed no correlation between PTP4A3 expression
in main mass and clinico-pathological parameters,
such as age, gender, location, invasion depth, histolog-
ical malignancy grade and classifications of Goseki
and Bormann (Table 1). An on the verge of statistical
significance relationship was noted between PTP4A3
expression and Lauren's classification (p=0.0503). The
intestinal type of carcinoma in most cases (31/47
cases) didn't show expression of PTP4A3 protein, but
the diffuse type of gastric carcinoma shown this
expression (14/24 cases). A statistically significant
relationship was also observed between PTP4A3
expression and Kubo's classification (p=0.0454).
According to the data presented in the table, positive
PTP4A3 expression was associated with poorly differ-
entiated mucoid carcinoma, carcinoma diffusum and
carcinoma diffusum anaplasticum. Also a very signifi-
cant correlation was found between local lymph node
involvement and positive PTP4A3 expression
(p<0.001). Positive PTP4A3 expression in the main
mass of tumour was detected in as many as 95,5%
(21/22 cases) of patients with lymph node involvement
whereas only 18,4% (9/49 cases) were free of lymph
node metastases. Patients' survival rate showed lack of
correlation with PTP4A3 expression (p=0.1808) (Fig-
ure 1).
Discussion
The study aimed to analyse the role of PTP4A3 protein
in gastric carcinoma in correlation with the presence of
lymph node involvement. As revealed by statistical
analysis, positive PTP4A3 expression is strongly asso-
ciated with metastases to local lymph nodes and their
633
Pryczynicz et al: PTP4A3 (PRL-3) Expression in Gastric Cancer.
©Polish Histochemical et Cytochemical Society
Folia Histochem Cytobiol. 2010:48(4): 633 (632-636)
Doi: 10.2478/v10042-010-0070-7
Page 2
extent, which seems to confirm earlier findings. Miskad
et al. [11] in an immunohistochemical study have
shown that high PTP4A3 expression is correlated with
lymph node metastases and their extent. Moreover, they
detected PTP4A3 expression in 92.6% of metastatic
lymph nodes. They also observed high protein expres-
sion in other metastases, e.g. to the liver and peri-
toneum, and PTP4A3 correlation with pT stage. They
additionally performed a study by hybridization method
in situ, confirming their earlier results associated with
metastases to lymph nodes. They also noted that high
PTP4A3 expression was associated with gender, tumour
634
A. Pryczynicz et al.
©Polish Histochemical et Cytochemical Society
Folia Histochem Cytobiol. 2010:48(4): 634 (632-636)
Doi: 10.2478/v10042-010-0070-7
Table 1. Relationship between PTP4A3 expression in primary lesion of gastric cancer and clinicopathological factors.
Relationship is significant at the level of p<0.05. Significant relationship is marked in bold.
*
w.d. well differentiated, m.d. moderately differentiated, p.d.
poorly differentiated, Ca carcinoma.
Page 3
size and metastasis via blood vessels. Patients with high
protein expression had worse prognosis, although their
survival did not correlate statistically with the expres-
sion [17]. Also Li et al. [18] obtained similar results
associating the role of PTP4A3 with local lymph node
metastases, their extent and T stage. Moreover, they
analysed cases of gastric carcinoma with metastases to
the peritoneum and found positive PTP4A3 expression
in as many as 80.9%. In their study, the protein expres-
sion also negatively correlated with patient's prognosis
– those with a lack of PTP4A3 expression had better
postoperative survival index. Wang et al. [19,20] con-
firmed a significant role of PTP4A3 protein in local
lymph node metastases. All these studies definitely indi-
cate that PTP4A3 protein has a major effect on gastric
carcinoma spread via the lymphatic pathway as com-
pared to colorectal carcinoma in which, according to
different literature sources, this protein has a role rather
in distant metastasizing. Most studies have indicated a
lack of significant role of PTP4A3 protein in local
lymph node metastases of colorectal carcinoma
[16,21,22].
Classification of gastric carcinomas according to
Goseki, Lauren, Bormann and Kubo allowed us to
identify a certain characteristic feature associated with
the presence of PTP4A3 expression. The diffuse type
of gastric carcinoma (according to the Lauren's micro-
scopic classification) showed a higher PTP4A3
expression (58%) as compared to the intestinal type.
Such a correlation, the same statistically insignificant,
was also observed in Bormann's classification. The
diffuse type of gastric cancer (macroscopic assess-
ment) showed positive PTP4A3 expression in 72.7%,
whereas in the remaining types (polypous, fungating
and ulcerative) positive expression was noted in a
small percentage of cases. The diffuse type infiltrates
flatly into the wall of the stomach and narrows its
lumen. It grows over a considerable area, is poorly dif-
ferentiated and gives metastases to lymph nodes.
Moreover, a statistically significant correlation was
noted between PTP4A3 expression and Kubo's classi-
fication. Poorly-differentiated mucoid carcinoma
showed positive PTP4A3 expression in 75% (6/8) of
cases, mucocellular carcinoma in 100% (1/1 case),
anaplastic diffuse carcinoma in 60% (3/5 cases),
whereas in other types the protein expression was
rather lacking. The analysis of the carcinomas accord-
ing to Goseki's classification revealed higher PTP4A3
expression in type II (58%) and IV (60%), i.e. in can-
cers with a large amount of mucus in their cells (a sta-
tistically insignificant finding). These two types of
gastric cancer are associated with worse prognosis
than types I and III.
Thus, PTP4A3 may play a major role in metastasis
via the lymphatic pathway. At the same time, as shown
by our study, PTP4A3 expression is also connected
with increased production of mucus by cancer cells. A
question thus arises whether and how the PTP4A3 pro-
tein affects this process as well as how it is associated
with mucous-producing cancer cells. Cai et al. [23]
have revealed that the mean survival time of the
patients is shorter when PTP4A3 expression is present
(18.9 months). Moreover, in their in vitro study,
decreased expression of PTP4A3 had an inhibitory
impact on the proliferation of cancer cells and tumour
growth. As shown in literature reports and our own
data, PTP4A3 plays a major role in metastasizing of
gastric cancer. Therefore, it seems useful to investigate
this protein as an early poorly prognosticating factor in
gastric cancer patients.
635
Pryczynicz et al: PTP4A3 (PRL-3) Expression in Gastric Cancer.
©Polish Histochemical et Cytochemical Society
Folia Histochem Cytobiol. 2010:48(4): 635 (632-636)
Doi: 10.2478/v10042-010-0070-7
Fig. 1. Survival curve of patients with gastric cancer. There was no
significant difference in overall survival rates between the patients
with present PTP4A3 expression in primary lesion and those with
absent PTP4A3 expression (p=0.1808).
Fig. 2. Expression of PTP4A3 in gastric cancer. Magnification
×400
Page 4
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Submitted: 8 April, 2010
Accepted after reviews: 15 July, 2010
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©Polish Histochemical et Cytochemical Society
Folia Histochem Cytobiol. 2010:48(4): 636 (632-636)
Doi: 10.2478/v10042-010-0070-7
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  • Source
    • "Afterwards, Wang et al. found that overexpression of PRL-3 was present in 47.7% of gastric carcinomas with the lymph node metastasis using monoclonal antibody [13] and reported its prognostic significance [13]. Although correlation between PRL-3 overexpression and lymph node metastasis or peritoneal metastasis has been reported at some aspects in gastric cancer [12,14], the identical expression in the primary tumors without metastasis, primary tumors with metastasis, and matched samples of primary lesion and liver metastasis has not been completely understood. Also, the prognostic value of PRL-3 expression has not been reached a consensus on its clinical significance. "
    [Show abstract] [Hide abstract] ABSTRACT: PRL-3 is a member of phosphatases of regenerating liver family, characterized by phosphatase active domain and C-terminal prenylation motif. Overexpression of PRL-3 has been implicated in multiple cancers. Here we examined the clinical significance of PRL-3 in gastric cancer together with its metastatic biological functions utilizing different structural mutants. PRL-3 expression was analyzed immunohistochemically in 196 gastric cancer patients and 21 cases of liver metastasis. A series of wild type PRL-3 or its mutant plasmids were expressed in BGC823 cells to investigate the relationship between its catalytic activity, cellular localization and metastatic potential in vitro. Positive staining of PRL-3 was observed in 19.4% (38/196) gastric cancer tissues compared with 76.2% (16/21) in liver metastasis. Statistical analysis revealed that PRL-3 expression correlated with lymph node metastasis and vascular invasion (P < 0.05). Patients with high PRL-3 expression showed poorer 5-year overall survival (P = 0.011). Wild type PRL-3 expressing cells resulted in enhanced migration and invasion ability, which were greatly crippled in form of PRL-3(C104S) or PRL-3(DeltaCAAX) mutants accompanied with its alteration in subcellular localization. Metastasis associated protein PRL-3 may serve as a potential prognostic biomarker in human gastric cancer. Both the phosphatase catalytic activity and cellular localization are critical for its function.
    Full-text · Article · Dec 2013 · Journal of Translational Medicine
  • Source
    • "Li et al. [25] reported that individuals with highly expressed PRL-3 have a significantly shorter survival than individuals with no or low expression genotype. However, some researchers such as Miskad et al. [27] and Pryczynicz et al. [29] failed to demonstrate any relationship between PRL-3 overexpression and survival in GC patients. These controversies in the predictive significance of the PRL-3 phenotype in GC warrant a quantitative meta-analysis of the study outcomes. "
    [Show abstract] [Hide abstract] ABSTRACT: Overexpression of phosphatase of regenerating liver 3 (PRL-3) has been implicated in gastric cancer (GC) metastasis. Epidemiological studies have evaluated the relationship between PRL-3 expression and prognosis in GC. However, results still remains controversial. In this study, a meta-analysis was performed to evaluate the association of PRL-3 expression with overall survival (OS) and clinicopathological characteristics. Literature databases were searched to identify eligible studies dated until April 2013. Summary hazard ratios (HRs) or odds ratios (ORs) with 95% confidence interval (95% CI) were calculated to estimate the association. A total of 1380 GC patients from six studies were included in the meta-analysis. Overall, the combined HR estimate for OS in a random-effect model was 1.89 (95% CI = 1.38-2.60; P<0.001). Results showed that PRL-3 overexpression was significantly associated with OS, indicating that it may be a biomarker for poor prognosis of GC. Both subgroup and sensitivity analyses further identified the prognostic role of PRL-3 expression in GC patients. Moreover, PRL-3 overexpression was significantly associated with tumor stage (OR = 2.25; 95% CI = 1.63-3.12; P<0.001), depth of invasion (OR = 2.03; 95% CI = 1.38-2.98; P<0.001), vascular invasion (OR = 2.52; 95% CI = 1.79-3.56; P<0.001), lymphatic invasion (OR = 3.74; 95% CI = 2.49-5.63; P<0.001), and lymph node metastasis (OR = 4.56; 95% CI = 2.37-8.76; P<0.001). However, when age, sex, tumor size, and tumor differentiation were considered, no obvious association was observed. This meta-analysis reveals significant association of PRL-3 overexpression with OS and some clinicopathological features in GC. PRL-3 may be a predicative factor of poor prognosis and aggressive tumor behavior in GC patients.
    Full-text · Article · Oct 2013 · PLoS ONE
  • Source
    • "Bardelli et al. [16] later showed that PRL-3 mRNA overexpression was not limited to liver metastases, but that PRL-3 was expressed more highly in all colorectal carcinoma metastases examined, regardless of the site of metastasis . PRL-3 overexpression has since been linked to such clinical parameters as disease progression , tumor aggressiveness, lymphatic invasion, venous invasion, presence and extent of metastasis , or poor patient prognosis in colon/ colorectal17181920, cervical [21], ovarian [22, 23], breast242526, gastric272829303132333435, non-small cell lung [36], esophageal [37], nasopharyngeal [12], brain [38], hepatocellular [39] and bile duct [40] cancers. These data suggest PRL-3 as a potential prognostic indicator of disease aggressiveness and clinical outcome for multiple tumor types. "
    [Show abstract] [Hide abstract] ABSTRACT: The PRL-1 and PRL-2 phosphatases have been implicated as oncogenic, however the involvement of these molecules in human neoplasms is not well understood. To increase understanding of the role PRL-1 and PRL-2 play in the neoplastic process, in situ hybridization was used to examine PRL-1 and PRL-2 mRNA expression in 285 normal, benign, and malignant human tissues of diverse origin. Immunohistochemical analysis was performed on a subset of these. PRL-1 and PRL-2 mRNA expression was also assessed in a small set of samples from a variety of diseases other than cancer. Where possible, associations with clinicopathological characteristics were evaluated. Alterations in PRL-1 or -2 expression were a frequent event, but the nature of those alterations was highly tumor type specific. PRL-1 was significantly overexpressed in 100% of hepatocellular and gastric carcinomas, but significantly under-expressed in 100% of ovarian, 80% of breast, and 75% of lung tumors. PRL-2 expression was significantly increased in 100% of hepatocellular carcinomas, yet significantly downregulated in 54% of kidney carcinomas. PRL-1 expression was correlated to patient gender in the bladder and to patient age in the brain and skeletal muscle. PRL-1 expression was also associated with tumor grade in the prostate, ovary, and uterus. These results suggest a pleiotropic role for PRL-1 and PRL-2 in the neoplastic process. These molecules may associate with tumor progression and serve as clinical markers of tumor aggressiveness in some tissues, but be involved in inhibition of tumor formation or growth in others.
    Full-text · Article · Jan 2012 · American Journal of Translational Research
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