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Does securin expression have significance in prognostication of oral tongue cancer? A pilot study

18 Apr 2016-European Archives of Oto-rhino-laryngology (Springer Berlin Heidelberg)-Vol. 273, Iss: 11, pp 3905-3911

TL;DR: Overexpression of securin was observed more frequently in advanced stages of OTSCC than in earlier stages but the difference was not statistically significant, suggesting that overeexpression of Securin may be important during progression of this cancer.
Abstract: The proliferation marker, securin, is involved in the progression of many carcinomas. However, its expression in oral tongue squamous cell carcinoma (OTSCC) has not been previously studied. We examined securin expression by immunohistochemistry in OTSCC. A total of 93 cases treated for OTSCC were included in this study. Expression of securin in OTSCC was studied by immunohistochemistry of tissue microarrays (52 cases) and routine tumor sections (41 cases). Securin overexpression is significantly associated with higher tumor grade (P = 0.03). Overexpression of securin was observed more frequently in advanced stages of OTSCC than in earlier stages but the difference was not statistically significant. These findings suggest that overexpression of securin in OTSCC may be important during progression of this cancer. No significant association was found between securin expression and the prognosis of OTSCC.
Topics: Securin (65%), CDC20 (50%)

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https://helda.helsinki.fi
Does securin expression have significance in prognostication of
oral tongue cancer? A pilot study
Heikkinen, Ilkka
2016-11
Heikkinen , I , Almangush , A , Hagström , J , Bello , I O , Kauppila , J H , Mäkinen , L ,
Haglund , C , Nieminen , P , Salo , T & Leivo , I 2016 , ' Does securin expression have
significance in prognostication of oral tongue cancer? A pilot study ' , European Archives of
Oto-Rhino-Laryngology , vol. 273 , no. 11 , pp. 3905-3911 . https://doi.org/10.1007/s00405-016-3964-y
http://hdl.handle.net/10138/228575
https://doi.org/10.1007/s00405-016-3964-y
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This is an electronic reprint of the original article.
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HEAD AND NECK
Does securin expression have significance in prognostication
of oral tongue cancer? A pilot study
Ilkka Heikkinen
1,2
Alhadi Almangush
1,2,3
Jaana Hagstro
¨
m
1,4
Ibrahim O. Bello
5
Joonas H. Kauppila
6,7
Laura K. Ma
¨
kinen
8
Caj Haglund
9,4
Pentti Nieminen
10
Tuula Salo
2,11,12,13
Ilmo Leivo
14,1
Received: 16 February 2016 / Accepted: 1 March 2016 / Published online: 18 April 2016
Ó Springer-Verlag Berlin Heidelberg 2016
Abstract The proliferation marker, securin, is involved
in the progression of many carcinomas. However, its
expression in oral tongue squamous cell carcinoma
(OTSCC) has not been previously studied. We examined
securin expression by immunohistochemistry in OTSCC. A
total of 93 cases treated for OTSCC were included in this
study. Expression of securin in OTSCC was studied by
immunohistochemistry of tissue microarrays (52 cases) and
routine tumor sections (41 cases). Securin overexpression
is significantly associated with higher tumor grade
(P = 0.03). Overexpression of securin was observed more
frequently in advanced stages of OTSCC than in earlier
stages but the difference was not statistically significant.
These findings suggest that overexpression of securin in
OTSCC may be important during progression of this can-
cer. No significant association was found between securin
expression and the prognosis of OTSCC.
Keywords Oral tongue squamous cell carcinoma
Prognosis Securin Expression
Introduction
Oral tongue squamous cell carcinoma (OTSCC) is the most
common epithelial malignancy of the oral cavity. The
incidence rates of OTSCC have increased over the last few
decades. Despite advances in cancer therapy, the prognosis
of OTSCC remains poor. This is mainly because of high
frequency of regional lymph node metastases that are not
uncommon even in early stages of the disease [1]. The
outcome of OTSCC varies greatly between different stages,
and cervical lymph node metastasis is probably the most
important prognostic marker so far [14]. During the last
decade, numerous molecular markers have been examined
& Ilmo Leivo
ilmo.leivo@utu.fi
1
Department of Pathology, University of Helsinki, Helsinki,
Finland
2
Department of Oral and Maxillofacial Diseases, University of
Helsinki, Helsinki, Finland
3
Institute of Dentistry, University of Misurata, Misurata,
Libya
4
Research Programs Unit, Translational Cancer Biology,
University of Helsinki, Helsinki, Finland
5
Department of Oral Medicine and Diagnostic Sciences, King
Saud University, Riyadh, Saudi Arabia
6
Department of Surgery, University of Oulu and Oulu
University Hospital, Oulu, Finland
7
Department of Pathology, University of Oulu and Oulu
University Hospital, Oulu, Finland
8
Department of Otorhinolaryngology and Head and Neck
Surgery, University of Helsinki and Helsinki University
Hospital, Helsinki, Finland
9
Department of Surgery, University of Helsinki and Helsinki
University Hospital, Helsinki, Finland
10
Department of Medical Informatics and Statistics, University
of Oulu, Oulu, Finland
11
Helsinki University Hospital, Helsinki, Finland
12
Research Group of Cancer Research and Translational
Medicine, Medical Faculty, University of Oulu, Oulu,
Finland
13
Medical Research Center, Oulu University Hospital, Oulu,
Finland
14
Department of Pathology, University of Turku, Turku,
Finland
123
Eur Arch Otorhinolaryngol (2016) 273:3905–3911
DOI 10.1007/s00405-016-3964-y

by immunohistochemistry in different cancers [5]. How-
ever, in OTSCC the expression of several important
markers remains to be determined. Therefore, further
studies on the molecular background of OTSCC are
required to understand tumor progression, to identify
prognostic markers and to recognize therape utic targets [6].
Cell proliferation is an important prognosticator in many
cancers, and there are ongoing efforts to recognize new
markers for it [7]. Securin is a proliferation marker enco-
ded by pituitary tumor transforming gene (PTTG1), and it
plays an important regulatory role in the cel l cycle through
blocking of mitosis [8]. Securin regulates the transition into
M-phase and it also plays a role in the adhesion of sister
chromatids, in the regulation of p53 and in DNA repair [9,
10]. Expression of securin has been studied in the devel-
opment, invasion and metastasis of various cancers.
Overexpression of securin has been suggested to promote
genetic instability in normal cells and in cancer cells [8,
11]. Genetic instability is one of the most important driving
forces in carcinogenesis [6]. In several human cancers,
overexpression of securin has been associated with poor
prognosis [8, 9, 12]. In oral squamous cell carcinoma
(OSCC), specifically, PTTG1 (which is identified as a
mammalian securin) was involved in early oral tumorige-
nesis [13], and its overexpression promotes inva sion [14].
Thus, we carried out this study to find out whether securin
could provide prognostic power in OTSCC. The relation-
ship of securin expression with clinical stage and
histopathological grade wer e also evaluated.
Materials and methods
Patients and tissue materials
Paraffin blocks of cancer tissues from 104 patients diag-
nosed with OTSCC at the University hospitals of Helsinki
(n = 60) and Oulu (n = 44) between 1981 and 2005 were
retrieved for this study.
Tissue microarrays (TMAs) were available from a pre-
vious study [ 15 ] and sections were cut from the paraffin
blocks. Six 1 mm cores were obtained from each tumor
with the tissue microarray instrument (Beecher Instru-
ments, Silver Spring, MD, USA). The cores were punched
from the central tumor area and from the most invasive
front of the tumor. Seventeen TMA slides with a total of 56
cores in 15 slides and 72 cores in two slides were prepared.
For the other 44 cases where TMA blocks were not
available, routine sections of normal size were cut for
immunohistochemistry, chosen from representative sec-
tions of each case. Tissue cores with \100 cancer cells
were excluded from this study as previously described [16].
Eleven cases were excluded due to unavailability of
clinical data or lack of tissue specimens; thus 93 cases were
included in the final analysis. The use of patient samples
and follow-up information were approved by the ethics
committees of Helsinki and Oulu university hospitals; and
by the National Supervisory Authority for Welfare and
Health (VALVIRA). Our study is retrospective, and for this
type of study formal consent is not required.
Securin immunohistochemistry
For immunohistochemistry, 4-lm thick sections were cut
from the tissue cores and treated according to the prot ocol.
Deparaffinization in xylene and rehydration in a graded
ethanol series and distilled water were performed. Antigen
recovery was performed in Tris–HCl buffer (pH 8.5) in a
PT-module (LabVision UK Ltd, UK) for 20 min at 98 °C.
Staining was performed in Autostainer 480 (LabVision)
with Dako REAL EnVision Detec tion System, Peroxidase/
DAB?, Rab bit/Mouse (Dako, Glostrup, Denmark). Sec-
tions were incubated in mouse monoclonal anti-securin
antibody (securin, clone DCS-280, ab3305; Abcam, Cam-
bridge, UK) with a dilution of 1:70 for 1 h; followed by
30-min incu bation in peroxidase-conjugated [Dako REAL
EnVision/HRP, Rabbit/Mouse (ENV)] reagent. Incubation
in Dako REAL DAB? Chromogen for 10 min was used to
visualize the antigen. Slides were counterstained with
Meyer’s hematoxylin. Finally they were covered with
xylene-based mounting medium in a glass coverslipper
(Dako Ltd, Copenhagen, Denma rk).
Evaluation of securin immunoexpression
The expression of securin was seen as a light or dark
brown staining reaction in the cytoplasm or in the nucl ei
of cancer cells. In the evaluation, we included both
nuclear and/or cytoplasmic expression and calculated the
average fraction of stained cells. Intensity of staining
reaction was not included in the scoring. The samples
were classified into five categories, based on the propor-
tion of cancer cells stained positively by securin anti-
bodies. Negative immunoexpression was scored as (0). If
less than 5 % of cancer cells were stained, the sample
was scored (1); C5to\10 % was scored (2); C10 to
\30 % was scored (3); and C30 % was scored (4). The
cores with the highest percentage of stained cancer cells
were considered representative for the expression of
securin in a particular tumor.
Two investigators (I.H. and A.A.) evaluated the samples
independently using Olympus BH-2 light microscope and
their scoring was reviewed by an experienced oral
pathologist (J.H.). In case of discrepancy, the samples were
re-evaluated for consensus. All observers were blinded to
patient data during evaluation.
3906 Eur Arch Otorhinolaryngol (2016) 273:3905–3911
123

Statistical analysis
The analyses were executed with IBM SPSS Statistics
(version 20). Evaluated samples were divided into low- and
high-risk categories according to expression of securin at
different percentage cut-off points (5, 10 and 30 %). The
differences in the expression of securin between early vs.
late stages of OTSCC and between low grade vs. inter-
mediate or high-grade tumors were calculated using Chi
square test.
Survival analysis was performed including overall sur-
vival (OS): the time from surgery to death or last follow-
up; disease-free survival (DFS): the time from surgery to
local and/or regional recurrence and/or distant metastasis;
disease-specific survival (DSS): the time from surgery to
death from OTSCC or to last follow-up.
Survival curves were constructed using the Kaplan–
Meier method and compared with log-rank test. Univariate
and multivariate analyses were performed with Cox-pro-
portional hazard model, using 95 % confidence interval
(CI). The analyses were carried out separately in early (T1/
T2) and advanced (T3/T4) cases as well as in all patients
jointly (T1 to T4). P values under 0.05 were considered
statistically significant.
Results
In clinical staging, the patients were distributed as follows:
T1 (23 patients), T2 (29 patients), T3 (36 patients) and T4
(5 patients). Fifty-one men and 42 women were included in
this study (Table 1). At the end of follow-up, 5 patients had
developed local recurrences, 10 had regional recurrences
and 9 had both local and regional recurrences. At that time,
38 patients were alive, 30 had died of OTSCC and 25 had
died of other causes.
Relationship between securin expression,
histopathological grade, clinical stage and survival
of OTSCC
In cases where securin was greatly overexpressed (C30 %)
(Fig. 1), its expression was consistently found to be more
common in moderately and poorly differentiated tumors
than in well-differentiated tumors (Table 2). This differ-
ence was found to be statistically significant (P = 0.03).
When our cases were divided based on a cut-off at 5 %, the
expression of securin C5 % was associated with tumors of
higher grade (Table 2), but this tendency did not reach
statistical significance (P [ 0.05). The same applied to
using 10 % as the cut-off point.
When the expression of securin was compared between
early and late stages of OTSCC, the latter showed higher
expression of securin (Table 3 ). Howeve r, the association
between overexpression of securin and advanced stages of
OTSCC did not reach statistical significance (P [ 0.05).
At any of the cut-off points (5, 10 or 30 %) of securin
expression, there was no statistically significant association
between the expression of securin and overall survival, dis-
ease-specific survival or disease-free survival (using Cox-
proportional hazard and log-rank test, P [ 0.05) (Fig. 2).
In multivariate analysis, the presence of cervical lymph
node metastases (pN-stage) was the only statistically signifi-
cant prognosticator for disease-specific survival (DSS) with a
hazard ratio (HR) of 3.89 (95 % CI 1.59–9.48, P = 0.003).
Similarly for overall survival (OS), the presence of recurrent
tumor in the lymph nodes was a significant predictor of poor
OS (HR of 2.36, 95 % CI 1.26–4.43, P = 0.007).
Discussion
The expression of securin has been examined in many
carcinomas (e.g. breast [8], esophageal [17] and rectal [18]
cancer). To the best of our knowledge, this is the first study
to examine the expression of securin in OTSCC. We
Table 1 Clinicopathologic characteristics of 93 patients with
OTSCC
Variable Number of cases %
Age
B60 years 52 55.9
[60 years 41 44.1
Gender
Male 51 54.8
Female 42 45.2
cT stage
T1 23 24.7
T2 29 31.2
T3 36 38.7
T4 5 5.4
Grade
Grade I 31 33.3
Grade II 44 47.3
Grade III 18 19.4
Securin (5 % expression)
Low (\5 %) 48 51.6
High (C5 %) 45 48.4
Securin (10 % expression)
Low (\10 %) 66 71.0
High (C10 %) 27 29.0
Securin (30 % expression)
Low (\30 %) 84 90.3
High (C30 %) 9 9.7
Eur Arch Otorhinolaryngol (2016) 273:3905–3911 3907
123

hypothesized that securin might have a prognostic value in
OTSCC. We found, however, no significant differences in
the survival between patients with low and high expression
of securin. Interestingly, we found that overexpression of
securin is significantly associated with higher tumor grade.
Overexpression of securin was also common in advanced
clinical stages of OTSCC.
The pituitary tumor transforming gene 1 protein,
securin, is an essential protein for separation of sister
chromatids [18, 19], and it is an inhibitor of separase
activity [10]. In normal tissues, securin was shown to have
a low level of expression [20], while overexpression of
securin has been reported in various cancers. Although the
role of securin in cancer progression is not well-under-
stood, it has been reported to play a role in apoptosis,
aneuploidy, angiogenesis, and regulation o f tumor
microenvironment [16, 21].
The prognostic value of traditional proliferation markers
such as Ki-67 and Mitotic Activity Index (MAI) has been
widely studied [22]. Recently, securin has been used as a
proliferation marker in a number of cancers. Interestingly,
Karra et al. [8] reported a strong prognostic power of
securin in predicting breast cancer mortality, and they
found that high expression of securin is a predictor of
aneuploid DNA content. In a later report [16], they showed
that a combination of high Cdc20 and high securin
expression may aid in the identification of breast cancer
patients with aneuploid DNA and poor progno sis. In
prostate cancer, securin overexpression has been reported
to cause an elevation in mitotic cells and apoptosis [23]. In
colorectal cancer, depletion of securin is reported to
enhance cell death and apoptosis [24]. Of note, Talvinen
et al. [22] reported that MAI and Ki-67 provide a b etter
reproducibility between observers than securin (although
Fig. 1 Securin expression in OTSCC. a Low: \30 % of cancer cells were stained with securin; b high: C30 % of cancer cells were stained
Table 2 Distribution of tumor
grades (I, II, III) in cases with
high securin expression
Grade I (31 cases) Grade II (44 cases) Grade III (18 cases)
High securin expression (C5 %) 12 (38.7 %) 22 (50 %) 11 (61.1 %)
High securin expression (C10 %) 5 (16.1 %) 15 (34.1 %) 7 (38.9 %)
High securin expression (C30 %) 0 (0 %) 5 (11.4 %) 4 (22.2 %)
The percentages refer to the proportion of high securin expression cases among each tumor grade category
Table 3 Distribution of early
and late stages of OTSCC in
cases with high securin
expression
Early stage (52 cases) Late stage (41 cases)
High securin expression (C5 %) 21 (40.4 %) 24 (58.5 %)
High securin expression (C10 %) 13 (25.0 %) 14 (34.1 %)
High securin expression (C30 %) 3 (5.8 %) 6 (14.6 %)
The percentages refer to the proportion of high securin expression cases among stage categories
3908 Eur Arch Otorhinolaryngol (2016) 273:3905–3911
123

Citations
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TL;DR: Although more exploratory research is needed with newer methods to identify biomarkers for TSCC, rigorous validation of biomarkers that have already shown unbiased assessment in at least two publications should be considered a high priority.
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References
More filters

Journal ArticleDOI
16 Jul 1999-Science
TL;DR: Human securin is identical to the product of the gene called pituitary tumor-transforming gene (PTTG), which is overexpressed in some tumors and exhibits transforming activity in NIH 3T3 cells, and the oncogenic nature of increased expression of vSecurin may result from chromosome gain or loss, produced by errors in chromatid separation.
Abstract: A vertebrate securin (vSecurin) was identified on the basis of its biochemical analogy to the Pds1p protein of budding yeast and the Cut2p protein of fission yeast. The vSecurin protein bound to a vertebrate homolog of yeast separins Esp1p and Cut1p and was degraded by proteolysis mediated by an anaphase-promoting complex in a manner dependent on a destruction motif. Furthermore, expression of a stable Xenopus securin mutant protein blocked sister-chromatid separation but did not block the embryonic cell cycle. The vSecurin proteins share extensive sequence similarity with each other but show no sequence similarity to either of their yeast counterparts. Human securin is identical to the product of the gene called pituitary tumor-transforming gene (PTTG), which is overexpressed in some tumors and exhibits transforming activity in NIH 3T3 cells. The oncogenic nature of increased expression of vSecurin may result from chromosome gain or loss, produced by errors in chromatid separation.

813 citations


"Does securin expression have signif..." refers background in this paper

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Daisuke Sano1, Jeffrey N. Myers1Institutions (1)
TL;DR: The promise of basing treatment decisions on biomarkers has yet to be fully realized because of poor understanding of the mechanisms of regional and distant metastases of SCCOT, and the potential of these studies to have a positive impact on the clinical management of S CCOT in the future is summarized.
Abstract: Squamous cell carcinoma of the oral tongue (SCCOT) is one of the most prevalent tumors of the head and neck region. Despite advances in treatment, the survival of patients with SCCOT has not significantly improved over the past several decades. Most frequently, treatment failure takes the form of local and regional recurrences, but as disease control in these areas improves, SCCOT treatment failures are occurring more often as distant metastasis. The presence of cervical lymph node metastasis is the most reliable adverse prognostic factor in patients with SCCOT, and extracapsular spread (ECS) of cervical lymph nodes metastasis is a particularly reliable predictor of regional and distant recurrence and death from disease. Decisions regarding the elective and therapeutic management of cervical lymph node metastases are made mainly on clinical grounds as we cannot always predict cervical lymph node metastasis from the size and extent of invasion of the primary tumors. Therefore, the treatment of these metastases in the management of SCCOT remains controversial. The promise of basing treatment decisions on biomarkers has yet to be fully realized because of our poor understanding of the mechanisms of regional and distant metastases of SCCOT. Here we summarize the current status of investigations of SCCOT metastases and the potential of these studies to have a positive impact on the clinical management of SCCOT in the future.

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TL;DR: Increased tumour PTTG1 expression may be a marker of invasive colorectal carcinoma and could represent a new therapeutic target.
Abstract: Summary Background Basic fibroblast growth factor promotes angiogenesis and mitogenesis in colon carcinomas. Pituitarytumour transforming gene ( PTTG 1 ) causes in-vitro and in-vivo transformation, regulates secretion of basic fibroblast growth factor, and inhibits chromatid separation. Most normal tissues show little or no PTTG 1 expression but cancer cells express the gene abundantly. We postulated that PTTG 1 expression in colorectal tumours is related to tumour invasiveness. Methods PTTG 1 gene and protein expression were assessed in 68 colorectal tumours and compared with invasive characteristics, such as lymph-node invasion, evidence of metastases, tumour vessel density, and expression of basic fibroblast growth factor. PTTG 1 expression is given in terms of the fold-increase over that in normal-adjacent colorectal tissue. Findings PTTG 1 was overexpressed in all of 48 colon carcinomas (median fold-increase 2·2 [IQR 1·8–3·3]) and in 19 of 20 colonic polyps (2·2 [1·6–3·1]) compared with normal colonic tissue. Invasion of surrounding lymph nodes was associated with higher PTTG 1 expression than in carcinomas limited to the bowel wall (3·4 [2·1–5·9] vs 1·9 [1·7–2·4], p=0·007), and higher PTTG 1 expression was seen in more vascular than in less vascular tumours (2·6 [1·9–5·1] vs 1·9 [1·8–2·5], p=0·04). Interpretation Increased tumour PTTG 1 expression may be a marker of invasive colorectal carcinoma and could represent a new therapeutic target.

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