Original Article

Iranian Journal of Otorhinolaryngology, Vol.28(1), Serial No.84, Jan 2016

MTA1 Expression in Benign and Malignant Salivary

gland Tumors
Azadeh Andisheh-Tadbir1, Ali Dehghani-Nazhvani2, Mohammad Javad Ashraf3,
Bijan Khademi4, Hosein Mirhadi5,*Shima Torabi-Ardekani2
Abstract
Introduction:
Salivary gland tumors (SGTs) are important parts of human neoplasms. The most common SGT is
pleomorphic adenoma and the most common malignant SGTs are mucoepidermoid carcinoma and
adenoid cystic carcinoma (ACC). Metastasis-associated genes 1 (MTA1), a member of the
nucleosome remodeling and histone deacetylation complex, is one newly discovered gene which
recruits histone deacetylation, causing ATP-dependent chromosome remodeling, and regulating
transcription. MTA1 had been shown to be overexpressed in malignant tumors with the
enhancement of invasion and metastasis.
Materials and Methods:
Fifty-six samples of salivary gland tumors from the Khalili Hospital archive, including 20 cases of
pleomorphic adenoma, 17 cases of mucoepidermoid carcinoma, 19 cases of ACC, and 23 cases of
normal salivary gland tissues were chosen for immunohistochemical analysis of MTA1.
Results:
MTA1 expression in the malignant tumors was significantly higher than that in pleomorphic
adenoma (P<0.001), and higher in pleomorphic adenoma than the normal salivary glands
(P< 0.001). In total, 69.6% of normal salivary gland tissues showed MTA1, but all cases of
salivary gland tumors were positive for MTA1. High nuclear expression of MTA1 was detected in
83.3% (30/36) of the malignant salivary gland tumors and 45% (9/20) of pleomorphic adenoma,
while low MTA1 expression was seen in all of the normal salivary gland tissues. No statistically
significant correlation was found between MTA1 protein expression and any clinicopathological
features (P>0.05).
Conclusion:
Our findings demonstrate that MTA1 was significantly overexpressed in malignant salivary gland
neoplasm in comparison to a lower level in benign pleomorphic adenoma, suggesting that MTA1
protein might be involved in carcinogenesis.
Keywords:
Adenoid cystic carcinoma, Salivary gland tumor, Mucoepidermoid carcinoma, MTA, Pleomorphic
adenoma.
Received date: 28 Feb 2015
Accepted date: 14 May 2015

1
Prevention of Oral and Dental Disease Research Center, Department of Oral and Maxillofacial Pathology,
School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran.
2
Department of Oral and Maxillofacial Pathology, School of Dentistry, Shiraz University of Medical Sciences,
Shiraz, Iran.
3
Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
4
Department of Otorhinolaryngology, Khalili Hospital, Shiraz Institute for Cancer Research, Shiraz University of
Medical Sciences, Shiraz, Iran.
5
Department of Endodontics, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran.
*
Corresponding Author:
Department of Oral and Maxillofacial Pathology, School of Dentistry, Shiraz University of Medical Sciences,
Shiraz, Iran. Tel: 0098-0713-6263193-4, E-mail: shima.torabi25@gmail.com

51
 Andisheh-Tadbir A, et al

Introduction Therefore, in this study we attempted to

Salivary gland tumors (SGTs) comprise 1– evaluate MTA1 expression in SGTs by
4% of all human neoplasms (1). The most using an immunohistochemical approach to
common tumor of salivary gland origin is establish correlation with tumor grade and
pleomorphic adenoma (PA), with an stage and to determine prognostic value.
incidence of 70% (2). Mucoepidermoid
carcinoma (MEC) and adenoid cystic Materials and Methods
carcinoma (ACC), with incidences of 35% I) Patients:
and 20%, respectively, are the most common In this study, 56 samples of salivary gland
malignant SGTs (3). Because of the various tumors from the Khalili Hospital archive,
histopathological features of SGTs and their Shiraz, Iran were reviewed, including 20
different clinical appearances and cases of PA, 17 cases of mucoepidermoid
morphologies, it is currently not possible to carcinoma and 19 cases of ACC. The control
define the prognosis of these tumors (4). group consisted of 23 cases of normal
The molecular mechanisms involved in the salivary gland tissues adjacent to the
development of SGTs are still unclear (4,5). previous biopsy of the oral cavity or SGT.
Malignant SGTs are slow growing but Of the 56 patients included in this study, 18
ACCs and high-grade MECs behave more (32.1%) were male and 38 (67.9%) were
aggressively because of perineural invasion, female. The mean age was 48.36±11.3
local recurrence, and distant metastasis. To (range 7–81) years. Tumor stages were
date, there is no definite indicator for the assessed based on the stages adapted by the
accurate determination of prognosis and American Joint Committee on Cancer
tumoral behavior (4). Therefore, it is (AJCC) TNM stage (11). Tumor grade in
necessary to find new molecular markers to MEC was classified as grade I if it
determine the prognosis and treatment of demonstrated a well-demarcated border,
SGTs (4). macrocystic spaces and a bland cyst lining;
Metastasis-associated genes (MTAs) are a grade II if it demonstrated a more solid
recently discovered family of genes with growth with only a few microcysts, and
three subtypes: MTA1, MTA2 and MTA3. focal infiltration; and grade III in the case of
MTA1 was first isolated by different no cystic spaces and a highly infiltrative
complementary DNA screening using the growth pattern, and pronounced nuclear
13762 NF rat mammary adenocarcinoma atypia. ACC grade I referred to tubular
metastatic cell line (6). growth pattern; grade II referred to
MTA1 is a component of nucleosome cribriform growth pattern; and grade III
remodeling and histone deacetylation referred to solid growth pattern (12).
complex (7), with a weight of 80 KDa (8),
recruiting histone deacetylation (7), causing II) Immunohistochemical staining and
ATP-dependent chromosome remodeling, analysis:
and regulating transcription (7,8). MTA1 First, hematoxylin and eosin slides of
controls epithelial-mesenchymal transition available blocks were reviewed, and cases
(8), which is one of the most important with a definite diagnosis and adequate
phenomena in invasion and metastasis. cellular tissue were selected for
Some authors have shown that MTA1 immunohistochemical staining (IHC). IHC
overexpression is accompanied by poor staining was performed by use of an
prognosis in malignant tumors (9), with the Envision-labelled peroxidase system
enhancement of invasion and metastasis (DAKO, Carpinteria, CA, USA). All
(10). However, to date there has been no samples were fixed in 10% buffered
investigation of MTA1 expression in SGTs. formalin and embedded in paraffin.

52 Iranian Journal of Otorhinolaryngology, Vol.28(1), Serial No.84, Jan 2016

MTA1 in Salivary gland Tumor

Sections of 5-μm thickness were prepared P<0.05 was considered statistically

and deparaffinized in histo-grade xylene, significant in all cases.
rehydrated in graded alcohol and washed Results
with distilled water. Antigen retrieval was Of the 56 patients included in this study, 18
performed using DAKO estimation and a (32.1%) were male and 38 (67.9%) were
target retrieval solution with pH=9, for 20 female. The mean age was 48.36±11.3
minutes. Internal peroxidase activity was (range 7–81) years; patients with PA were
inhibited by 3% H2O2. the youngest (mean, 42.4±16.2 years) and
Tissue sections were then incubated for 60 patients with MEC were the oldest (mean,
minutes with the anti-MTA1 monoclonal 57.7±14.4 years). Most tumors (60.7%)
antibody (mouse, Abcam Corporation, ab involved the major salivary glands.
84136, UK) at 1/400 dilution. MTA1 expression in normal salivary gland
Brown nuclear or cytoplasmic staining for and salivary gland tumor:
MTA1 was considered as positive. Omission Both cytoplasmic and nuclear patterns were
of the primary antibody was employed as a seen in both normal salivary gland tissue and
negative control, while oral squamous-cell SGTs. In the normal salivary gland tissue,
carcinoma tissue known to overexpress MTA1 staining was positive in 16 cases
MTA1 protein was used as a positive control (69.6%).
for MTA1 protein staining. MTA1 expression was seen in the
MTA1 immunoreactivity was evaluated epithelial lining of the salivary duct and also
using a semiquantitative scoring system for in mucous and serous acini (Fig.1).
both the percentage of positively stained
cancer cells (0: 0–5%, 1: 6–25%, 2: 26–
50%, 3: 51–75%, 4: >76%) and the staining
intensity (0, negative staining; 1, weak
staining; 2, moderate staining; 3, intense
staining).
The total score was the multiplication of
the scores of the staining intensity and
percentage of positive cells, and was graded
as follows: 0,1, 2, 3, 4, 6, 8, 9, or 12. Tumors A
with a final staining score >6 were defined
as having high MTA1 expression, while
tumors with scores ≤6 were defined as
having low MTA1 expression (13).

III) Statistical analysis:

A Mann-Whitney test, Kruskal Wallis test,
Chi-Square test, Spearman´s correlation
coefficient test and Fisher’s Exact test were
used to compare the result between groups
B
and the relation with clinical-pathological
features such as tumor size, metastasis to Fig 1: MTA-1 expression in duct and acini of
lymph nodes, distant metastasis, tumor grade normal salivary gland tissues (A: ×200) (B: ×400).
and tumor stage. We used the SPSS18 MTA1 immunoreactivity was seen in all
software to statistically analyze the data. A (100%) the SGTs. In PA, both ductal and

Iranian Journal of Otorhinolaryngology, Vol.28(1), Serial No.84, Jan 2016 53

B
 Andisheh-Tadbir A, et al

myoepithelial cells showed MTA1 staining In MEC, the epidermoid cells, mucous
(Fig. 2). cells, and intermediate cells displayed
positive staining. Solid areas with
predominant epidermoid cells revealed a
high expression (Fig.4).

B
Fig2: MTA-1 expression in ductal and myoepithelial
cells of pleomorphic adenoma (×200).

All histological variants of ACC showed

MTA1 positivity (Fig.3).

Fig 4: MTA-1 expression in mucoepidermoid

carcinoma (A: ×100) (B: ×400).

High nuclear expression of MTA1 was

detected in 83.3% (30/36) of the malignant
SGTs and 45% (9/20) of PA, while low
MTA1 expression was seen in all of the
A normal salivary gland tissues (Table.1).
Types Number High Low MTA1
of of MTA1 expression
lesion patients expression N (%)
N (%)
ACC 19 17 (89.5) 2(10.5)
MEC 17 13(76.5) 4(23.5)
PA 20 9 (45) 11 (55)
Normal 23 0 (0) 23 (100)

MTA1 expression in the malignant tumors

was significantly higher than that in PA
B (P<0.001), and it was higher in PA than in
the normal salivary glands (P<0.001). In
Fig 3:MTA-1 expression in ACC (A:×200)(B: ×400). ACC, 89.5% (17/19) cases showed high

54 Iranian Journal of Otorhinolaryngology, Vol.28(1), Serial No.84, Jan 2016

MTA1 in Salivary gland Tumor

nuclear expression of MTA1, while in MEC, salivary gland tumors:

76.5% (13/17) showed high MTA1 Our data showed no statistically significant
expression. No significant difference was correlation between MTA1 protein
seen between MEC and ACC (P>0.05). expression and any clinicopathological
Correlation between MTA1 expression and features (P>0.05) (Table. 2).
the clinicopathological features of malignant
Table 2: Clinicopathologic characteristics of the 56 patients with salivary gland tumors.
MTA1 protein MTA1 protein
Variable N (%) (high expression, total (low expression, total P. Value
score >6)N (%) score ≤6)N (%)
Gender
Male 18 (32.1%) 15 (83.3%) 3 (16.7%) 0.53
female 38 (67.9%) 24 (63.2%) 14 (36.8%)
Age 48.3 ± 11.3 – – 0.04
T-status
MEC
T1+T2 10 (58.8) 7 (70) 3 (30)
T3+T4 7 (41.2) 6 (85.7) 1 (14.3) 0.19
ACC
T1+T2 10 (52.6) 8 (80) 2 (20) 0.4
T3+T4 9 (47.4) 9 (100) 0 (0)
N status
MEC
N0 14 (82.3) 10 (71.4) 4 (28.6) 0.5
N1 3 (17.7) 3 (100) 0 (0)
ACC
N0 16 (84.2) 14 (87.5) 2 (12.5) 0.7
N1 3 (15.8) 3 (100) 0 (0)
M status
MEC
M0 15 (88.2) 11 (73.3) 4 (26.7) 0.5
M1 2 (11.8) 2 (100) 0 (0)
ACC
M0 18 (94.7) 16 (88.9) 2 (11.1) 0.8
M1 1 (5.3) 1 (100) 0 (0)
Stage
MEC
I+II 8 (47.05) 5 (62.5) 3 (37.5) 0.2
III+IV 9 (52.95) 8 (88.9) 1 (11.1)
ACC
I+II 9 (47.4) 7 (77.8) 2 (22.2) 0.2
III+IV 10 (52.6) 10 (100) 0 (0)
Grade
MEC
I 7 (41.2) 4 (57.1) 3 (42.9) 0.2
II 10 (58.8) 9 (90) 1 (10)
ACC
I 5 (26.3) 4 (80) 1 (20) 0.3
II 13 (68.4) 12 (92.3) 1 (7.7)
III 1 (5.3) 1 (100) 0 (0)

Iranian Journal of Otorhinolaryngology, Vol.28(1), Serial No.84, Jan 2016 55

 Andisheh-Tadbir A, et al

Discussion tumor progression. P53 is an important

Salivary gland neoplasms are important tumor-suppressor gene and causes apoptosis.
parts of head and neck lesions (3), but they It is deacetylated by MTA1, which results in
are rare and comprise only 3–10% of head repression of P53 activity in non-small-cell
and neck tumors (14). Salivary gland lung cancer and hepatoma (20).
neoplasms have morphological diversity and Another mechanism of the MTA1 function
wide heterogeneity, so their diagnosis and is in relation to hypoxia-induced factor-1α
classification are challenging (15). SGTs (HIF-1α). MTA1 increases the expression of
with the same histopathological features or histone deacetylase-1 and causes
stage have different clinical behavior, and deacetylation of HIF-1α, which is involved
therefore, different prognoses (16). Thus, in tumor angiogenesis (21). MTA1 can also
finding new biomarkers that are correlated bind to HIF-1α and deacetylated HIF-1α and
with tumor prognosis and treatment protocol cause expression of VEGF-A and VEGF-C,
is necessary. which is associated with metastasis (21,22)
MTA1 was primarily isolated by different and lymphangiogenesis, respectively
complementary DNA screening using the rat (23,24). MTA1 is a marker of epithelial-
metastatic breast carcinoma (17). MTA1 is a mesenchymal transitions (EMTs). EMTs are
coregulatory factor and acts in cellular necessary for embryonic development and
signaling and remodeling of chromosomes, cancer progression (25).
and also has transcriptional activity, so it is As discussed above, MTA1 can also be
involved in progression, growth, and expressed in normal tissue at lower levels.
invasion of metastatic epithelial cells (9). MTA1 at a physiological level may regulate
MTA1 has been shown to be overexpressed differentiation and EMT (17). However,
in various human cancers and involved in further studies are required to clarify the
tumor invasion, higher metastatic potential exact role of MTA1 in normal tissues.
and advanced clinical stage (18). This study Kawasaki found higher MTA1 levels in
for the first time tried to evaluate MTA1 oral SCC, which was correlated with more
expression and its prognostic role in SGTs. advanced stage and higher rates of
We found that MTA1 immunoreactivity in metastasis to lymph nodes (26). Toh et al.
malignant tumors was significantly higher found that a high level of MTA1 protein was
than PA and higher in PA than in the normal associated with depth of tumor invasion,
salivary gland tissues (nSGTs). This finding higher pathologic stage, and metastasis to
suggests that MTA1 is involved in the lymph nodes in esophageal SCC (18). Li et
carcinogenesis of SGTs and reflects the al. showed that MTA1 overexpression is
aggressive nature of these malignant tumors correlated with lymph-node metastasis and
when compared with PA. These findings are TNM staging in non-small-cell lung
in accordance with the higher levels of carcinoma, but not with the clinical and
MTA1 seen in ovarian cancer in comparison histopathological subtypes of tumor (27). In
with normal ovarian epithelium (13). a recent study, the authors showed that
Some other investigations have also found MTA1 overexpression in esophageal cancer
higher levels of MTA1 in malignant was correlated with T-status, but no
neoplasms such as prostate cancer, gastric significant correlation was identified with
cancer, esophageal and renal cancer than in clinical and histopathological status (28).
normal tissues (19). The mechanisms of In the present study, we evaluated the
MTA1 function have been studied correlation between MTA1 level and
extensively. MTA1 affects various clinical-pathological factors such as tumor
biomolecules and causes carcinogenesis and size, grade, stage and metastasis to lymph

56 Iranian Journal of Otorhinolaryngology, Vol.28(1), Serial No.84, Jan 2016

MTA1 in Salivary gland Tumor

nodes. However, we found no correlation in the mucous glands, myoepithelial cells or

between MTA1 overexpression and ductal epithelium (35). However, we found
clinicopathological factors. Although MTA1 both cytoplasmic and nucleus staining in the
overexpression was seen in patients with ductal epithelium and in serous and mucous
advanced tumor size and clinical stage, the glands. Predominantly cytoplasmic
difference between groups was not expression of MTA1 in the serous and
statistically significant, which may be mucous acini of the nSGTs in this study may
because of the low number of cases in our reflect the non-genomic function of MTA1.
study. Moon et al. reported nuclear and MTA1, master coregulatory biomarker,
cytoplasmic localization of MTA1 in human could be a novel target for cancer therapy,
hepatocellular carcinoma (HCC) (29). helping to determine the diagnosis and
Balasenthil et al. also found both nuclear and prognosis of tumors (7). The clinical
cytoplasmic staining for MTA1 in benign efficiency of targeting MTA1 biomolecules
endometrial glands, but in endometrial has not yet been proven, but several studies
carcinoma they showed that MTA1 was have suggested MTA1 protein or gene as a
predominantly localized to cytoplasm in molecular target for cancer therapy (7).
grade III tumor, suggesting that in this grade, MTA1 has also been shown to stimulate T-
MTA1 had a non-genomic function (30). cell response in patients with cancer (36).
MTA1 was shown to have markedly nuclear Toh et al. also showed that restraining of
positivity in some cancerous tissue, such as MTA1 function or expression augmented
lung cancer, gastric, colorectal and ovarian the sensitivity of cancer cells to
cancer (31). In our previous study, we chemotherapy by retrieving function of P53
demonstrated both nuclear and cytoplasmic as a tumor-suppressor gene or by preventing
localization of MTA1 in oral SCC (32). tumor angiogenesis by stabilizing HIF-1α
In the present study, we found both nuclear (7). Therefore MTA1 is a good target for
and cytoplasmic expression of MTA1 in diagnosis, prognosis, and therapy of human
SGTs and nSGTs. Earlier investigations cancers; but more studies are needed to
stated that MTA1s, a short version of intensively evaluate its role in cancer
MTA1, is located in the cytoplasm, binding therapy and its possible clinical use.
to ER-α and inhibiting its nuclear function Our study had some limitations, such as an
by transforming it to cytoplasm in breast inadequate number of total cases, lack of
cancer cells (33); thus, non-genomic access to follow up and survival of the
function of ER-α occurs in the cytoplasm, patients, and the small number of cases with
such as stimulation of MAPK (33). metastasis to the lymph nodes or distant
Li et al. found cytoplasmic expression of metastasis. We were, therefore, unable to
MTA1 in normal adult hepatocytes of the evaluate the correlation between MTA1
mouse, but after hepatectomy, its protein level and metastasis.
expression was predominantly nuclear.
This may have been because of the Conclusion
translocation of MTA1 from the cytoplasm The present study is the first to evaluate the
to the nucleus to play a transcriptional role role of MTA1 in benign and malignant
and in stimulation of proliferation for salivary gland neoplasms and compare them
hepatic regeneration (34). with nSGTs. Our findings demonstrate that
Li et al. (2008) evaluated MTA1 in the MTA1 was significantly overexpressed in
salivary gland in a mouse model and found malignant salivary gland neoplasm in
nuclear localization with weak staining comparison with a lower levels in benign
intensity in the serous glands, but no staining PA, suggesting that MTA1 protein might be

Iranian Journal of Otorhinolaryngology, Vol.28(1), Serial No.84, Jan 2016 57

 Andisheh -Tadbir A, et al

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