Expression of Yin Yang 1 in cervical cancer and its correlation with E-cadherin expression and HPV16 E6
Expression of Yin Yang 1 in cervical cancer and its correlation with E-cadherin expression and HPV16 E6
Wanxue Wang 1 2 3
Zhenni Yue 0 1 3
Zhengping Tian 1 3
Yiran Xie 1 3
Jiamiao Zhang 1 3
Yuanping She 0 1 3
Bing Yang 0 1 3
Yuan Ye 0 1 3
Yihua Yang 1 2 3
0 Department of Obstetrics and Gynecology, the Affiliated Hospital of Guilin Medical College , Guilin , China
1 Funding: These studies were supported by the National Natural Science Foundation of China (Grant No. 81360386 and No.81560245 to Yihua Yang) and the Natural Science Foundation of Guangxi Province (Grant No.2015GXNSFAA139182 to Yihua Yang). The funders had no role in study design , data collection
2 Center of Reproductive Medicine, the first Affiliated Hospital of Guangxi Medical University , Nanning , China , 2 Center of Reproductive Medicine, the Affiliated Hospital of Guilin Medical College , Guilin , China
3 Editor: Xuefeng Liu, Georgetown University , UNITED STATES
The molecular mechanisms of normal cervical squamous epithelium advancing to cervical intraepithelial neoplasia (CIN) and eventually to cervical squamous cell carcinoma (CSCC) are largely unknown. This study explored abnormal expression of Yin Yang 1 (YY1) in cervical cancer and its correlation with the expression of E-cadherin and human papillomavirus (HPV) 16 E6. YY1, E-cadherin and HPV16 E6 expression were detected by immunohistochemistry in 90 cervical tissue specimens collected from 30 patients with hysteromyoma, 15 patients with CIN I, 15 patients with CIN II-III, and 30 patients with CSCC. The H-score method was employed to measure the expression of YY1, E-cadherin and HPV16 E6. Increased expression of YY1 and HPV16 E6, and the decreased expression levels of E-cadherin were strongly associated with malignant transformation of the cervical epithelium and the histological progression of CSCC. The expression of YY1 in cervical tissues was inversely correlated with E-cadherin expression, and positively correlated with HPV16 E6 expression. Expression of YY1 in CSCC tissues was not significantly correlated with tumor differentiation, but was significantly correlated with an advanced clinical stage of CSCC. These results suggest that up-regulation of YY1 is closely associated with the progression of CSCC, and YY1 may play an important role in the pathogenesis of cervical cancer by modulating the expression of E-cadherin and HPV16 E6.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Cervical cancer is a common malignancy in women, of which the most frequent pathological
type is cervical squamous cell squamous carcinoma (CSCC). Current research suggests that
cervical cancer pathogenesis is associated with the persistent infection of high-risk human
papillomavirus (HPV) [
]. However, the pathogenesis of cervical cancer is a complex process,
which involves multiple genes and gene-factors, thus, high-risk persistent HPV infection is not
the only factor in cervical cancer progression and pathogenesis. Apart from high-risk HPV
and analysis, decision to publish, or preparation of
infection, studies have demonstrated that various tumor-suppressors, oncogenes and tumor
growth factors are involved in these disease processes [
]. In China, the incidence and
mortality of cervical cancer remains high, and the age of cervical cancer onset tends to be younger
]. In this regard, cervical cancer has become a serious threat to female health. Investigation
of cellular factors involved in the pathogenesis and progression of cervical cancer may provide
novel strategies for management of this malignancy.
Yin Yang 1 (YY1) is a ubiquitously distributed transcriptional factor belonging to the
GLI-Kruppel class of zinc finger proteins. YY1 can act as either transcriptional activators or
repressors in gene expression regulation [
]. YY1 was found to be oncogenic in various
types of cancers, such as breast cancer, prostate cancer and lymphomas [
studies have shown that YY1 is up-regulated in cervical cancer [
] in addition to negatively
regulating the expression of E-cadherin in the pathogenesis of breast cancer [
acts as a tumor-suppressor and is critical for the formation and maintenance of adherent
junctions in areas of epithelial cell-cell contact. Most tumors have abnormal cellular architecture,
and loss of tissue integrity leads to local invasion. Thus, loss of E-cadherin critical cellular
function correlates with increased invasiveness and metastasis of tumors [
]. Recent studies
have demonstrated that low E-cadherin expression is a negative, independent prognostic
factor in patients with cervical cancer .
The HPV16 E6 gene has been shown to be one of major oncogenes in high-risk persistent
HPV infection and closely associated cervical cancer pathogenesis. HPV16 E6 serves as an
important biomarker for the development of cervical cancer. Mechanistically, HPV16 E6 was
found to promote the pathogenesis and progression of cervical cancer via complex
mechanisms, such as suppressing p53 expression, regulating Daxx expression, and enhancing
telomerase activity [15±17]. Studies have demonstrated that YY1 negatively regulates the HPV16 E6
expression in cervical cancer [
], suggesting that YY1 may target many downstream effectors
to regulate the pathogenesis and progression of cervical cancer.
Effects of YY1 on the expression of E-cadherin and HPV16 E6 has been documented in
previous studies [
]. Previously, we also demonstrated the novel miR-193a-5p-YY1-APC
regulatory axis in regulation of endometrioid endometrial adenocarcinoma progression ,
however, to the best of our knowledge, the expression of YY1, E-cadherin and HPV16 E6, as
well as the correlations between them, have not been reported on normal cervical tissues,
cervical intraepithelial neoplasia (CIN) tissues and CSCC tissues. In this study, the expression of
YY1, E-cadherin and HPV16 E6 in normal cervical tissues, CIN tissues and CSCC tissues was
determined by immunohistochemistry (IHC). The correlations between YY1 and E-cadherin
as well as HPV16 E6 were also analyzed. Our findings may provide new insights into
understanding YY1-mediated pathogenesis of cervical cancer.
Materials and methods
Patients and clinical samples
A total of 90 patients, 30 patients with hysteromyoma, 15 patients with CIN I, 15 patients with
CIN II-III, and 30 patients with CSCC were enrolled in this study. CIN or CSCC tissues were
collected from patients with CIN or CSCC receiving cervical biopsy and hysterectomy, and
normal cervical tissues were collected from patients with hysteromyoma receiving
hysteromyoma resection, and all the patients were HPV 16 DNA positive. The clinical characteristics
of patients are described in the results section. All the clinical samples were collected between
May 2013 and April 2015 at the Affiliated Hospital of Guilin Medical University. All clinical
specimens were kept in tissue paraffin blocks. Each pathological diagnosis was reviewed in a
double-blind manner by two experienced pathologists. The clinical stage of cervical cancer was
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defined according to criteria from the International Federation of Gynecology and Obstetrics
in 2009 [
]: 12 cases were diagnosed as Stage IA-IB1, and 18 cases were diagnosed as Stage
IB2IIA. With regards to tumor differentiation, 13 cases were well or moderately differentiated, and
17 cases were poorly differentiated. Patients who were pregnant, or who had received a
previous cervical therapy or preoperative treatment, or who were diagnosed other types of
malignancies were excluded for the study. This study was reviewed and approved by the Ethics
Committee of the First Affiliated Hospital of Guilin Medical University, and written informed
consent was obtained from all patients.
Sections measuring 4-μm were sectioned from the paraffin-embedded cervical tissue sample
blocks. The tissue sections were de-paraffinized in xylene for 10 min, fixed using 100% ethanol
for 5 min, and then dehydrated with 95%, 85% and 75% ethanol. Antigen retrieval was
performed by placing the tissue sections in sodium citrate buffer (for YY1 and E-cadherin
detection) or ETDA buffer (for HPV16 E6 detection). Application of a high voltage for 3 min was
then followed by natural cooling. Endogenous peroxide activity was reduced by placing the
tissue sections in the 3% hydrogen peroxide in methanol for 10 min at room temperature. The
sections were then washed twice with phosphate buffered saline (PBS) and incubated with the
primary antibodies: mouse anti-YY1 monoclonal antibodies (1:100, Santa Cruz, Dallas, USA),
rabbit anti-E-cadherin polyclonal antibodies (1:100, Santa Cruz), rabbit anti-HPV16 E6
polyclonal antibodies (1:100, Santa Cruz) overnight at 4ÊC. The sections were then washed with
PBS and incubated with corresponding secondary antibody for 30 min at room temperature.
The sections were then rinsed with PBS and incubated with diaminobenzidine (DAB)
chromogen for 3±5 min. Finally, the slides were counterstained with 10% hematoxylin, and stained
images were captured using a microscope with a digital camera.
Immunoreactive score (H-score)
The specimen signal strength was scored manually by two experienced pathologists using
histology slide images under 400x microscope and the following scale: 0, no signal above
background; 1, weak signal; 2, moderate signal; and 3, strong to very strong signal. H-score was
calculated using the following formula: H-score = (% cells not stained × 0) + (% cells stained
weak × 1) + (% cells stained moderate × 2) + (% cells stained strong × 3).
All the statistical analyses were performed by using the statistical software, SPSS version 18.0
(Chicago, USA). Significant difference between two groups were analyzed by t-test, and
significant difference among more than two groups was analyzed by one-Way ANOVA. The
correlation analysis was performed using the Spearman rank correlation test. P<0.05 was considered
General clinical characteristics of the recruited subjects
In the present study, 30 women from control group were 32±52 years old with a mean age
of 43.60 ± 5.35. In the CIN group, age ranged from 26±46 years old with a mean age of
42.93 ± 5.35 years old; and in the CSCC group age ranged from 37±59 years old with a mean
age of 40.67 ± 6.29 years old. No significant difference was found between these subject groups
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Fig 1. Protein expression patterns of YY1, E-cadherin and HPV16 E6 in cervical tissues. Representative images of immunohistochemistry (400x) for (A) YY1,
(B) E-cadherin and (C) HPV16 E6 in normal cervical tissues.
Expression of YY1, E-cadherin and HPV16 E6 in cervical tissues
The expression of YY1, E-cadherin and HPV16 E6 were detected by IHC. The negative control
images with corresponding isotypes (YY1, E-cadherin and HPV16 E6) were shown in S1 Fig.
YY1 expression was detected in all tissues examined, and the expression of YY1 was mainly
located in the nucleus (Fig 1A). E-cadherin was also detected in all tissues examined, and its
expression mainly located in the cell membrane (Fig 1B). For HPV16 E6 expression, the
expression of HPV16 E6 was mainly found in the cytosol (Fig 1C), and the HPV16 E6
expression was detected in 81.1% (73/90) of all tissues examined, 66.67% (20/30) in the normal tissue
group, 83.33% (25/30) in the CIN group, and 93.33% (28/30) in the CSCC group.
The expression of YY1, E-cadherin, and HPV16 E6 H-scores were compared between the
normal tissue group, CIN group and CSCC group. As shown in Fig 2A, there was no
significant difference in YY1 expression between the normal group and the CIN I group (P>0.05),
and the expression of YY1 in the CIN II-III group was significantly higher than that in normal
group and CIN I group (P<0.05). The expression of YY1 in the CSCC group was also
significantly higher than that in the normal group and the CIN I group (P<0.05), while no significant
difference was detected in terms of YY1 expression between the CIN II-III group and the
Fig 2. Summary of YY1, E-cadherin, HPV16 E6 H-score results in cervical tissues from different histological groups. H-scores for (A) YY1, (B) E-cadherin
and (C) HPV16 E6 in normal group (n = 30), CIN I group (n = 15), CIN II-III group (n = 15) and CSCC group (n = 30). Significant differences between groups
were shown as P<0.05, P<0.01 and P<0.001. NS = not significant.
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Fig 3. Protein expression patterns of YY1 in cervical tissues. Representative images of immunohistochemistry (400x) for YY1 in (A) normal cervical group, (B)
CIN group, and (C) CSCC group.
CSCC group (P>0.05). The representative IHC images of YY1 in normal tissue, CIN and
CSCC groups are shown in Fig 3.
The expression results of E-cadherin are presented in Fig 2B, where there is significant
difference of E-cadherin expression between CIN I and CIN II-III groups (P>0.05). The
expression of E-cadherin in both CIN I and CIN II groups were significantly lower than that of the
normal group (P<0.05). Additionally, the expression of E-cadherin in the CSCC group was
significantly lower than that in normal, CIN I and CIN II-III groups (P<0.05). The
representative IHC images of E-cadherin in normal, CIN, and CSCC groups were present in Fig 4.
The expression of HPV16 E6 was also compared among different tissue groups. As shown
in Fig 2C, the expression of HPV16 E6 in CIN II-III group was significantly higher than in
normal group and CIN I group (P<0.05). While there was no significant difference detected in
terms of HPV16 E6 expression between normal and CIN I groups (P>0.05). The expression of
HPV16 E6 in CSCC group was also significantly higher than that in the normal group and
CIN I group (P<0.05), while no significant difference for HPV16 E6 expression was found
between CIN II-III group and CSCC group (P>0.05). Fig 5 presents representative IHC
images of HPV16 E6 in control, CIN, and CSCC groups.
Correlation between YY1 expression and, E-cadherin or HPV16 E6,
expression in cervical tissues
The correlation between YY1 expression and, E-cadherin or HPV16 E6 expression in all
cervical tissues was analyzed by Spearman's rank correlation test. As shown in Table 1, YY1
Fig 4. Protein expression patterns of E-cadherin in cervical tissues. Representative images of immunohistochemistry (400x) for E-cadherin in (A) normal group,
(B) CIN group, and (C) CSCC group.
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Fig 5. Protein expression patterns of HPV16 E6 in cervical tissues. Representative images of immunohistochemistry (400x) for HPV16 E6 in (A) normal group,
(B) CIN group, and (C) CSCC group.
expression was negatively correlated with E-cadherin expression in all cervical tissues
examined (r = -0.523, P<0.001). However, YY1 expression was positively correlated with HPV16 E6
expression in all cervical tissues examined (r = 0.444, P<0.001). Representative images of
sequential sections for YY1 and E-cadherin staining in control, CIN, and CSCC groups is
shown in Fig 6.
Fig 6. Protein expression patterns of YY1 and E-cadherin in cervical tissues. The representative images of sequential sections (400x) for YY1 in (A) normal
group, (B) CIN group, and (C) CSCC group, and E-cadherin in (D) normal group, (E) CIN group, and (F) CSCC group.
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Well or moderately differentiated
Correlation between YY1 expression and clinical pathological factors in
The CSCC group was divided into two groups based on tumor differentiation i.e. well or
moderately differentiated vs. poorly differentiated. There was no significant difference in YY1
expression between the two groups (Table 2, P = 0.7631). In addition, the CSCC group was
also divided into two groups according to FIGO stage i.e. IA-IB1 vs. IB2-IIA. The expression of
YY1 in IB2-IIA group was significantly higher than that in IA-IB1 group (Table 2, P<0.001).
Spearman's rank correlation analysis further revealed that the YY1 expression was not
significantly correlated with tumor differentiation (r = 0.7744, P>0.05), while its expression was
positively correlated with more advanced FIGO stage (r = 0.6771, P<0.001).
YY1 is a ubiquitously distributed transcriptional factor that belongs to the GLI-Kruppel class
of zinc finger proteins, and it is located in the telomeres of chromosome 14q32.2. YY1 can act
as either a transcriptional activator or transcriptional repressor in gene expression regulation
]. Mounting evidence from cancer studies has revealed that YY1 is involved cell cycle
regulation, cell proliferation and apoptosis as well as modulation of oncogenes and
tumor-suppressor genes expression . YY1 was found to be involved in tumor invasion and migration
by regulating the epithelial-mesenchymal transition (EMT) process, and YY1 promoted EMT
in tumor cells via NF-κB/Snail/YY1/RKIP/PTEN signaling [
]. The abnormal expression of
YY1 has been reported in various types of cancers, and its abnormal expression has been
linked to poor prognosis in cancer patients [
]. Overexpression of YY1 predicted poor
prognosis in breast cancer and non-Hodgkin lymphoma, while the YY1 overexpression was found
to be inversely correlated with poor prognosis in prostate cancer [
]. Studies have also
demonstrated up-regulation of YY1 in the cervical cancer [
], which implicates YY1
overexpression in poor prognosis prediction in cervical cancer.
In the present study, the expression of YY1, E-cadherin and HPV16 E6 in normal cervical
tissues, CIN tissues and CSCC tissues at histological level using IHC for the first time. The
correlation between YY1 and E-cadherin/HPV16 E6 expression was also explored. YY1 was
expressed in the cell nucleus, in agreement with its functional role as a transcriptional
regulator. We also found that YY1 was up-regulated in CSCC tissues when compared to normal
cervical or CIN I tissue, suggesting a potential relationship between YY1 and the pathogenesis of
cervical cancer. The expression of YY1 in CSCC tissues was positively correlated with advance
FIGO stage, but was not correlated with the tumor differentiation, suggesting that YY1 may
also be associated the CSCC infiltration.
E-cadherin belongs to the cadherin protein family and is mainly expressed in the
membrane of the epithelial cells. It is critical for the formation and maintenance of adherent
junctions in areas of epithelial cell-cell contact. E-cadherin is an important tumor suppressor and
down-regulation of E-cadherin can promote EMT, a critical process for the metastasis and
invasion for malignant tumors originating in the epithelial [
]. As an important regulator of
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EMT, loss of E-cadherin suppresses cell adhesion and polarity, which promotes EMT in tumor
cells. Studies have suggested that E-cadherin may serve as an important biomarker for tumor
malignancy, metastasis, recurrence and prognosis in cervical cancer [
In the present study, E-cadherin was found in the cell membrane of all the cervical tissues
examined, meaning E-cadherin may be related to cell adhesion mediation. Our results
demonstrated that E-cadherin expression in CSCC tissues was significantly lower than that in normal
cervical tissues and CIN tissues. Additionally, down-regulation of E-cadherin may suppress
cell adhesion and promote EMT, which can subsequently enhance tumor invasion and
metastasis in CSCC. In our study, though no significant difference for E-cadherin expression
between CIN I and CIN II-III groups was detected, the expression of E-cadherin in CIN II-III
group tended to be higher than in the CIN I group. This finding is contrary to hypothesis that
decreased E-cadherin expression is inversely correlated with increased malignancy in cervical
cancer. Such a contradiction may be explained by the limited number of samples and
variations in H-scores, thus, in future studies, more clinical samples should be examined to confirm
the relationship between E-cadherin expression and progression of cervical cancer.
The expression of E-cadherin is regulated by various cellular factors in the tumor. The
promoter region of human E-cadherin contains two E-box, and Snail competitively binds to
Ebox as a promoter, which in turn suppresses the expression of E-cadherin. In addition,
MMP9 has been found to suppress the expression of E-cadherin [
]. In breast cancer, YY1
suppresses the expression of E-cadherin via NF-κB/Snail/YY1/RKIP/PTEN signaling [
], as well
as via the methylation process [
]. In this regard, we hypothesized that YY1 suppresses the
expression of E-cadherin in cervical cancer. In the present study, we found that the expression
of YY1 was negatively correlated with the expression of E-cadherin. These findings imply that
YY1 promotes tumor metastasis in cervical cancer via suppression of E-cadherin expression.
The underlying molecular mechanism involving the interaction between YY1 and E-cadherin
may require further investigations.
HPVs are a group of circular dsDNA viruses that infect epithelia cells, and recipient cell
entering the M phase is critical for the infection of HPV [
], and HPV-DNA integration into
cellular chromatin is usually for pathogenesis in HPV-related cancer [
]. The HPV16 E6
protein is the major proto-oncogenic protein of this virus; it is involved in many critical
pathogenesis pathways in cervical cancer. Studies have shown that HPV16 E6 can bind to E6 associated
protein (E6AP) to form the E6-E6AP complex; the E6-E6AP complex subsequently binds to
p53, causing it to degrade [
]; HPV 16 E6 expression inhibited the stabilization of p53 and
promoted tumorigenesis via genome destabilization [
]. In addition, HPV 16 E6 protein
can bind Bak to stimulate Bak degradation and reduce Bak-induced apoptosis, which may
contribute to the oncogenic potential of the virus [
]. Studies from Klingelhutz et al., also showed
that HPV16 E6 protein can induce telomerase activation [
]. Evidence from animal studies
showed that HPV E6 and E7 proteins acted synergistically to cause head and neck cancer in
]. Additionally, studies have reported that the E-cadherin promoter is repressed in
cells expressing HPV16 E6, resulting in fewer E-cadherin transcripts. E-cadherin regulation by
HPV16 E6 has been suggested to contribute to viral immune evasion, as adhesion between
keratinocytes and the epidermal antigen presenting cells are E-cadherin-mediated [
Additional studies have also shown that HPV16 E6 regulates the expression of E-cadherin via
targeting Wnt/β-catenin signaling pathway [
]. HPV16 E6 was shown to activate human
telomerase reverse transcriptase, which was suggested as an important mechanism of HPV16
E6-mediated tumorigenesis [
Our results demonstrated that the expression of HPV16 E6 in CSCC tissues was higher
than that in normal cervical and CIN I tissues, suggesting that HPV16 E6 may be involved
in the CSCC pathogenesis. In addition, the expression of HPV16 E6 in CIN II-III tissues
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was higher than that in CIN I tissues, but was similar to those levels found in CSCC tissues,
suggesting that patients with CIN II-III may have high-risk of progressing into CSCC.
Correlation analysis further revealed that the expression of YY1 in CSCC tissues was
positively correlated with expression of HPV16 E6, suggesting that YY1 can promote the
expression of HPV16 E6 in cervical cancer pathogenesis. In in vitro study, YY1 was found to
repress HPV16 E6 promoter by quenching the AP-1 activity in HeLa cells [
the E6 promoter of extrachromosomal HPV16 DNA in cervical cancer escaped cellular
repression by mutating YY1 target sequences [
]. Further experimentation suggested that
mutation of YY1-motifs long control regions is one of the mechanisms for enhancement of
HPV oncogene expression during cancer cell progression [
]. More mechanistic studies
should be performed to clarify this discrepancy about the interaction between YY1 and
In summary, the present study demonstrated that the abnormal expression of YY1,
E-cadherin and HPV16 E6 were associated with cervical squamous cell carcinoma progression.
There was a negative correlation between YY1 expression and E-cadherin expression, and
positive correlation between YY1 expression and HVP16 E6 expression in cervical cancer tissues.
These results suggest that YY1 may play an important role in the development of cervical
cancer by modulating the expression of E-cadherin and HPV16 E6.
S1 Fig. Negative control staining images for YY1, E-cadherin and HPV16 E6 in cervical
tissues. Representative images (400x) of isotype controls for YY1 staining in (A) normal cervical
group, (B) CIN group, and (C) CSCC group; representative images (400x) of isotype controls
for E-cadherin staining in (D) normal cervical group, (E) CIN group, and (F) CSCC group;
representative images (400x) of isotype controls for HPV16 E6 staining in in (G) normal
cervical group, (H) CIN group, and (I) CSCC group.
S2 Fig. Ethics approval Page 1.
S3 Fig. Ethics approval Page 2.
S4 Fig. Ethics approval Page 3.
Conceptualization: Wanxue Wang, Yuan Ye, Yihua Yang.
Data curation: Wanxue Wang, Zhenni Yue, Zhengping Tian, Yihua Yang.
Formal analysis: Zhenni Yue, Zhengping Tian, Yiran Xie, Jiamiao Zhang, Yuanping She, Bing
Yang, Yihua Yang.
Funding acquisition: Yihua Yang.
Methodology: Bing Yang.
Supervision: Yuan Ye, Yihua Yang.
Investigation: Wanxue Wang, Zhenni Yue, Zhengping Tian, Yihua Yang.
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Writing ± original draft: Yihua Yang.
Writing ± review & editing: Yiran Xie, Jiamiao Zhang, Yuanping She, Bing Yang.
10 / 12
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