The clinicopathological significance of UBE2C in breast cancer: a study based on immunohistochemistry, microarray and RNA-sequencing data
Mo et al. Cancer Cell Int
The clinicopathological significance of UBE2C in breast cancer: a study based on immunohistochemistry, microarray and RNA-sequencing data
Chao‑hua Mo 0 2
Li Gao 0 2
Xiao‑fei Zhu 0 1 2
Kang‑lai Wei 0 2
Jing‑jing Zeng 0 2
Gang Chen 0 2
Zhen‑bo Feng 0 2
0 Department of Pathology, The First Affiliated Hospital of Guangxi Medical University , 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region , China
1 Department of Pathology, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou Worker's Hospital , 1 Liushi Road, Liuzhou 545005, Guangxi Zhuang Autonomous Region , China
2 Department of Pathology, The First Affiliated Hospital of Guangxi Medical University , 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autono‐ mous Region , China
Background: Ubiquitin‑ conjugating enzyme E2C (UBE2C) has been previously reported to correlate with the malignant progression of various human cancers, however, the exact molecular function of UBE2C in breast carcinoma (BRCA) remained elusive. We aimed to investigate UBE2C expression in BRCA and its clinical significance. Methods: The expression of UBE2C in 209 BRCA tissue samples and 53 adjacent normal tissue samples was detected using immunohistochemistry. The clinical role of UBE2C was analyzed. Public databases including the human protein atlas and Oncomine were used to assess UBE2C expression in BRCA. Moreover, the cancer genome atlas (TCGA) database was employed to investigate the prognostic value of UBE2C in BRCA. Results: The positive expression rate of UBE2C in BRCA was 70.8% (148/209), and UBE2C expression in the adjacent breast tissue was negative. The expression of UBE2C was positively correlated with tumor size (r = 0.32, P < 0.001), histological grade (r = 0.237, P = 0.001), clinical stage (r = 0.198, P = 0.004), lymph node metastasis (r = 0.155, P = 0.026), HER2 expression level (r = 0.356, P < 0.001), Ki‑ 67 expression level (r = 0.504, P < 0.001), and P53 expression level (r = 0.32, P = 0.001). Negative correlations were found between UBE2C expression and the ER (r = − 0.403, P < 0.001) and PR (r = − 0.468, P < 0.001) status. UBE2C gene expression data from the public databases all proved that UBE2C was overexpressed in BRCA. According to the TCGA data analysis, a higher positive expression of UBE2C was associated with worse survival of BRCA patients (P = 0.0428), and data from cBioPortal indicated that 11% of all sequenced BRCA patients possessed a gene alteration of UBE2C, predominately gene amplification and mRNA regulation. Conclusion: Ubiquitin‑ conjugating enzyme E2C might pose an oncogenic effect on the progression of BRCA.
Breast cancer; Ubiquitin‑ conjugating enzyme E2C; Immunohistochemistry; Public database; Clinico‑ pathological significance; Gene alteration
Breast carcinoma (BRCA) is one of the most common
malignant neoplasms in humans and has a high
cancerrelated morbidity in females, ranking 6th in mortality
for females [
]. BRCA is a highly heterogeneous
], and the mechanism underlying its initiation
and development remains unclear. Therefore, the
identification of biomarkers for early diagnosis, prognosis
judgment and treatment of BRCA is urgently needed.
Ubiquitin-conjugating enzyme E2C (UBE2C), a crucial
part of the ubiquitin-conjugating enzyme complex, is
involved in the ubiquitin–proteasome system. The
ubiquitin–proteasome pathway is one of the main pathways
of protein degradation in eukaryotes and serves as an
important component in the post-translational
modification of proteins. The process of ubiquitination is
associated with many biological processes [
]. In recent
studies, the dysregulation of the ubiquitination process
has been discovered to play essential roles in the
occurrence and progression of cancers, and ubiquitination has,
thus, become a new therapeutic target for cancer [
Previous studies have reported overexpression of UBE2C
in some cancers such as colorectal carcinoma ,
pancreatic carcinoma [
], cervical cancer [
], esophageal squamous cell carcinoma [
and lung cancer, etc. [
]. Particularly, cancers with a
high degree of malignancy, low differentiation and high
metastatic tendency usually present with higher UBE2C
expression and poor patient survival [
several studies have confirmed UBE2C overexpression in
BRCA and the prognostic significance of UBE2C in
], the specific role and molecular
mechanism of UBE2C expression in BRCA is unclear. Therefore,
in this study, we employed immunohistochemistry (IHC)
and bioinformatics analysis guided by public databases
containing data on gene expression in cancer to detect
UBE2C expression in BRCA and adjacent tissues.
Moreover, we investigated the clinico-pathological significance
of UBE2C expression in BRCA and endeavored to
elucidate the molecular mechanism underlying it.
Materials and methods
We collected archived wax blocks of 209 pathologically
diagnosed infiltrating ductal breast carcinoma tissues and
53 corresponding adjacent tissues that were 5 cm away
from the tumor edges in Liuzhou Worker’s Hospital
during the period of January 2013 to March 2015. All of the
patients were females ranging from 31 to 81 years old with
a median age of 50 years. The clinico-pathological
information of the 209 infiltrating ductal carcinoma tissue samples
is listed in Table 1. Study protocol was approved by The
Ethical Committee of First Affiliated Hospital of Guangxi
Medical University. All the patients signed the written
informed consents before participating in the study.
The rabbit anti-human monoclonal antibody against
UBE2C (1:100 dilution) was purchased from the Abnova
Co., ltd. Fast enzyme-labeled Goat anti-mouse/rabbit IgG
polymer, citrate buffer, phosphate buffer saline (PBS) and
diaminobenzidine (DAB) indicator were all purchased
from Fuzhou Maixin Biotechnology Development Co.,
ltd. Apart from the rabbit anti-human monoclonal
antibody against UBE2C, the following antibodies were
used in IHC: rabbit anti-human HER2 monoclonal
antibody (EP3, Fuzhou Maixin Biotechnology Development
Co., ltd), rabbit anti-human P53 monoclonal antibody
(SP5, Fuzhou Maixin Biotechnology Development Co.,
ltd), rabbit anti-human ER monoclonal antibody (SP1,
Fuzhou Maixin Biotechnology Development Co., ltd),
rabbit anti-human PR monoclonal antibody (SP2, Fuzhou
Maixin Biotechnology Development Co., ltd) and mouse
anti-human Ki67 monoclonal antibody (MIB-1, Fuzhou
Maixin Biotechnology Development Co., ltd). All of the
specimens were fixed with 10% neutral formaldehyde
solution and embedded in paraffin. Hematoxylin–eosin
staining and immunohistochemical staining were
performed on 4-μm-thick sliced tissue sections.
Immunohistochemistry in two-step was performed following the
operating instructions of the kit to examine the
expression of UBE2C, HER2, P53, ER, PR and Ki-67. The
positive control for the UBE2C staining was normal human
placenta tissue, and PBS instead of the first antibody was
used as the blank control.
Evaluation of immunohistochemical staining
The positive UBE2C signal was localized to the nucleus
and cytoplasm. The staining intensity was scored as
follows: 0 for no staining, 1 for canary yellow, 2 for yellow
and 3 for brown. The percentage of positive cells was
subdivided into four groups: 0 for less than 5%, 1 for 6–25%,
2 for 26–50%, 3 for 51–75% and 4 for more than 75%.
Multiplication of the two scores provided the final
immunohistochemistry score. The eventual determination of
the results was defined as follows: 0 for negative (−), 1–2
for weak positive (+), 3–4 for positive (++) and ≥ 5 for
strong positive (+++) [
]. According to the 2013 ASCO/
CAP guidelines, moderate or strong HER2 expression in
10% of the tumor cell membranes was considered as HER2
]. As for p53, strong nuclear staining in at least
10% of the tumor cells was regarded as positive [
positive result for ER and PR staining was defined as
positive nuclear reactivity in at least 1% tumor cells [
Negative and positive Ki-67 immunostaining corresponded
to < 14% and ≥ 14% of the Ki-67 positive tumor cells,
]. With regard to the interpretation of all
the immunostaining results, 1000 cells from ten randomly
selected high-power visual fields were counted by two
pathologists independently. When the difference between
evaluation results from the two pathologists was more
than 10%, the immunostaining results were re-evaluated.
Bioinformational analysis of UBE2C expression from public database
To validate the IHC results, UBE2C expression in
BRCA and normal tissues was obtained from the HPA
database. The HPA database is a huge repository of
transcriptome and proteome data generated from
RNAsequencing analysis and immunohistochemistry analysis,
which reflected the important value of the HPA database
in protein expression analysis [
]. In this study, we
compared the UBE2C expression in BRCA samples as well as
the immunohistochemical results originating from three
normal patients and 20 BRCA patients.
We further explored UBE2C expression in different types
of BRCA in the Oncomine database. Oncomine is a cancer
microarray database that allows researchers to mine
webbased data of genome-wide expression in various types
of human cancers and corresponding normal tissues [
]. We compared the pattern of UBE2C expression in
nine major types of BRCA including ductal BRCA, lobular
BRCA, mixed lobular and ductal BRCA, intra-ductal
cribriform breast adenocarcinoma, male BRCA, breast
phyllodes tumor, tubular BRCA and medullary BRCA. P < 0.05
and fold change > 1.5 were selected as the threshold.
Firebrowse contains large-scale omics data from
multiplatforms and is an advantageous tool for analyzing cancer
gene expression in human cancers [
]. In this study, the
distribution of UBE2C expression in different types of
cancer was analyzed from Firebrowse (http://www.firebrowse.
org/viewGene.html?gene=UBE2C), and a box plot based on
UBE2C expression in diversified human cancers and
corresponding normal tissues was downloaded from Firebrowse.
TCGA data analysis of UBE2C expression and its gene alteration in BRCA
The prognostic significance of UBE2C expression in BRCA
We also investigated the prognostic value of UBE2C
expression in BRCA using survival data of 503 BRCA
patients with low UBE2C expression and 503 BRCA
patients with high UBE2C expression from Oncolnc
(http://www.oncolnc.org/). Kaplan–Meier survival
curves were created in Oncolnc to assess the impact of
UBE2C expression on the prognosis of BRCA patients.
Gene alteration of UBE2C in BRCA tissue from cBioPortal
We used cBioPortal (http://www.cbioportal.org) to inquire
into the gene alteration status of UBE2C in BRCA [
OncoPrint schematic was constructed in cBioPortal (TCGA
provisional) to directly reflect all types of alterations such
as amplification, deep deletion, mRNA up-regulation, and
mRNA down-regulation in the UBE2C gene from 1098
BRCA patients. Alteration frequency of the UBE2C gene
in BRCA tissues from different sources was visualized in a
histogram comparing the distribution of UBE2C gene
alterations in different subtypes of BRCA. Additionally, Kaplan–
Meier survival curves were drawn in cBioPortal to evaluate
the influence of gene alterations of UNE2C on the overall
and disease-free survival of the 1098 BRCA patients. To
achieve a comprehensive understanding of the
UBE2C-centered gene regulation network, the gene network of the UBE
family and the neighboring genes was generated in
cBioPortal for the analysis of the interaction between these genes.
Statistical analysis for IHC
We conducted χ2 tests to assess the expression of UBE2C in
BRCA and para-carcinoma tissues as well as the
relationship between UBE2C expression and the
clinico-pathological variables of BRCA. Correlation analysis was performed
by using the Spearman correlation test. Kaplan–Meier
survival curves were drawn to compare the survival rates
between UBE2C-positive BRCA cases and UBE2C-negative
BRCA cases. Multivariable Cox hazard regression analysis
was performed to assess the impact of clinico-pathological
variables on the prognosis of BRCA. P < 0.05 was
considered statistically significant. All of the statistical analyses
stated above were performed in SPSS v.21.0
The difference in UBE2C expression between BRCA and adjacent tissues
The clinical pathological features of all the 209 BRCA
patients were summarized in Table 1. UBE2C achieved a
positive staining rate of 70.8% (148) of the 209 BRCA
samples. Among the positively stained cases, there were 57, 67
and 24 cases of weak positive staining, positive staining,
and strong positive staining, respectively.
UBE2C-negative staining was found in the remaining 61 BRCA tissues.
Conversely, all of the adjacent tissues presented negative
UBE2C staining. Thus, UBE2C expression was remarkably
higher in BRCA tissues than in adjacent tissues. The
difference in UBE2C expression between BRCA and adjacent
tissues was statistically significant (P < 0.05) (Table 2, Fig. 1).
The association between UBE2C expression in BRCA and the clinico‑pathological features of BRCA
UBE2C expression in BRCA was significantly related to
histological grade, tumor size, lymph node metastasis
n = 209
n = 53
χ2 test was conducted to assess the expression of UBE2C in BRCA and adjacent tissues
BRCA breast carcinoma
Positive (+ to +++) (%)
and clinical stage (P < 0.05). However, there was no
significant relationship between UBE2C expression
in BRCA and the age or distant metastasis of cancer
(P > 0.05) (Table 3).
UBE2C expression in different molecular types of BRCA
As shown in Table 4, the UBE2C-positive expression
rates were 29.0% (18/62), 72.7% (24/33), 90.9% (30/33),
95.2% (40/42) and 92.3% (36/39) in Luminal A BRCA,
Luminal B (HER2−) BRCA, Luminal B (HER2+) BRCA,
HER2-overexpression BRCA and triple-negative BRCA,
respectively. The statistical results suggested that the
positive expression rate of UBE2C was the highest in
HER2overexpression BRCA tissue, followed by triple-negative
BRCA tissue, while the expression rate of UBE2C was the
lowest in Luminal A BRCA tissue. There was a significant
difference between UBE2C expression in various
molecular types of BRCA (P < 0.05) (Table 4).
Spearman correlation test
Correlation analyses revealed that the expression level of
UBE2C in BRCA was positively associated with the
following factors: tumor size (r = 0.32, P = 0.000),
histological grade (r = 0.237, P = 0.001), clinical stage (r = 0.198,
P = 0.004), lymph node metastasis (r = 0.155, P = 0.026),
HER2 expression (r = 0.356, P = 0.000), Ki-67
expression (r = 0.504, P = 0.000) and P53 expression (r = 0.32,
P = 0.001). Additionally, a negative correlation was
found between UBE2C expression in BRCA and
estrogen (ER) (r = − 0.403, P = 0.000) and progesterone (PR)
(r = − 0.468, P = 0.000) expression.
The influence of UBE2C expression on BRCA patient prognosis
The follow-up period began at the operation time and
ended on April 16, 2016. The end time for the dead
patients was the time of death. The longest follow-up
χ2 test was conducted to evaluate the correlation between UBE2C expression and the clinico-pathological parameters of BRCA
time was 1183 days, and the shortest follow-up time
was 37 days. There were completed data from 8 patients
that died of BRCA and censored data from 201 cases,
including 184 patients still alive at the end of the
followup period and 17 cases lost to follow-up. Among the
209 BRCS cases, there were 61 UBE2C-negative BRCA
samples and two deaths. The mean survival time was
1155.316 days with a 95% confidence interval of 1117.394
to 1193.235 days. The survival curves showed that there
was no significant difference between the survival rates of
the two groups of patients with different UBE2C
expression (P = 0.738, data not shown). Further
multivariable Cox hazard regression analysis indicated no obvious
effect of UBE2C on the prognosis of BRCA patients
(HR = 0.535, 0.055–5.169, P = 0.589) (Table 5).
Bioinformational analysis of UBE2C expression from public database
According to data from the HPA database, UBE2C
exhibited low expression in three cases of normal breast tissue
and high expression in 20 samples of BRCA tissue. The
Fig. 3 UBE2C expression in subtypes of ductal BRCA and normal tissues from Oncomine. The contrast between UBE2C expression in invasive ductal
BRCA and normal breast tissues was more obvious (P = 0.006, P = 7.08E−10, a, b) than that in ductal BRCA in situ and the matched normal tissues
(P = 0.022, P = 4.79E−5, c, d)
Fig. 4 UBE2C expression in lobular BRCA and normal tissues from Oncomine. Compared with the difference in UBE2C expression between lobular
BRCA tissues and normal tissues (P = 0.035, c; P = 8.05E−7, d), the difference between UBE2C expression in invasive lobular BRCA and normal tis‑
sues was more significant (P = 0.020, a; P = 1.87E−17, b)
immunohistochemical staining of UBE2C expression in
normal breast tissues and BRCA tissues are displayed in
As shown in Figs. 3, 4, 5, and 6, there was a general
trend of higher UBE2C expression in all types of BRCA
tissues than in the paired normal tissues (all P < 0.05).
Specifically, the difference in UBE2C expression between
cancer tissues and the paired normal tissues was more
significant with the increased malignancy of the same
type of BRCA. For example, the contrast between UBE2C
expression in invasive ductal BRCA and normal breast
tissues was more obvious (P = 0.006, P = 7.08E−10,
Fig. 3a, b) than that between ductal BRCA in situ and the
matched normal tissues (P = 0.022, P = 4.79E−5, Fig. 3c,
d). A similar pattern of UBE2C expression in BRCA and
normal tissues was also observed in lobular BRCA and
mixed ductal and lobular BRCA (Figs. 4, 5). Moreover,
UBE2C expression was remarkably higher in other types
of BRCA such as male BRCA (P = 4.73E−6), tubular
BRCA (P = 1.02E−25), mucinous BRCA (P = 3.46E−18)
and medullary BRCA (P = 5.16E−25) (Fig. 6) compared
with that in normal breast tissues. In addition, we
compared UBE2C expression in ductal carcinoma and other
types of breast cancer. UBE2C expression in ductal
carcinoma was higher than most other types of breast
cancer (Fig. 7a–d, all P < 0.05) except breast
adenocarcinoma with squamous metoplasla and medullary breast
The box plot in Fig. 8 from Firebrowser illustrates that
UBE2C expression was universally higher in most human
cancers, including BRCA, than in normal tissues.
TCGA data analysis of UBE2C expression and its gene alteration in BRCA
The prognostic significance of UBE2C expression in BRCA
Kaplan–Meier survival analysis of data from Oncolnc
revealed that BRCA patients with lower UBE2C
expression had a better prognosis than BRCA patients with
higher UBE2C expression (P = 0.0428) (Fig. 9).
Gene alteration of UBE2C in BRCA tissue from cBioPortal
From the OncoPrint schematic, gene alteration of
UBE2C was shown to occur in 118 (11%) of all the 1098
sequenced cases, which included 30 cases of
amplification, one case of deep deletion, 19 cases of mRNA
down-regulation and 80 cases of mRNA up-regulation.
Specifically, a mixed type of amplification and mRNA
up-regulation were observed in 12 cases (Fig. 10a).
Statistical results of the gene alteration frequency
indicated that a UBE2C gene alteration occurred in than
5% of most BRCA tissues, except for BRCA tissues from
BRCACRC xenografts (Fig. 11). Among the BRCA cases
with gene alteration of UBE2C, amplification occupied
the overwhelming majority of alteration types (Fig. 11).
We further evaluated the relationship between gene
alteration of UBE2C and the survival of BRCA patients.
However, both Kaplan–Meier survival curves for
overall survival and disease-free survival showed that there
was no significant correlation between gene alteration
of UBE2C and the overall survival or the disease-free
survival of BRCA patients (Fig. 10b, c). To shed light
on the underlying mechanism of UBE2C expression in
BRCA, a gene regulation network containing UBE2C
and the 50 most frequently altered neighboring genes
was constructed. As illustrated by the network, part of
the 50 most frequently altered neighboring genes such
as ASB7, ARIH2, and KLHL20 form a complex with
UBE2C. Some other genes including PSMD12, TRIM11,
SMURF2 and PSMD8 interact directly with UBE2C
Breast carcinoma is one of the most common malignant
neoplasms that pose a serious threat to women’s life and
health. It is of great importance to delve into the
pathogenesis of BRCA and identify molecular biomarkers for
BRCA with high sensitivity and specificity. UBE2C, as
a crucial member of the ubiquitin-conjugating enzyme
family (E2), plays a pivotal role in the
ubiquitin–proteasome proteolytic (UPP) pathway. Disorder of the UPP
pathway initiates abnormal degradation of proteins
encoded by some oncogenes and tumor suppressor
genes, subsequently leading to abnormal accumulation of
these proteins in the body. Therefore, the UPP system is
closely related to the occurrence and progression of
]. With respect to the relationship between
UBE2C and BRCA, Parris et al. observed higher
expression of UBE2C in invasive BRCA tissues than in
normal breast tissues . The prognostic value of UBE2C
has also been validated to be significant in high-risk
early BRCA and node-positive BRCA samples [
In the research conducted by Rawat et al., the
suppression of UBE2C could inhibit growth of BRCA cells and
sensitized breast cancer cells to radiation, doxorubicin,
tamoxifen and letrozole . Despite the above
findings, the exact function and molecular basis of UBE2C in
BRCA has remained elusive. We have, for the first time,
comprehensively investigated the protein expression and
gene alteration of UBE2C in BRCA as well as the
clinicopathological significance of UBE2C in BRCA using a
combination of immunohistochemistry (IHC) and
excavation of gene expression data from public databases.
To test the hypothesis that UBE2C exerts a
carcinogenic influence on BRCA, we first detected UBE2C
expression in BRCA and matched normal tissues by
using IHC. The results from our
immunohistochemistry experiments showed that highly positive UBE2C
expression in BRCA tissues contrasted sharply with the
negative UBE2C expression in adjacent tissues. In
addition, the expression of UBE2C was positively correlated
with histological grade, tumor size, clinical stage and
lymph node metastasis of BRCA. In vitro experiment
in previous articles have also proved that UBE2C could
enhance the proliferative, viability and invasive
capacity through MTT, colony formation assay and invasion
assays in lung cancer and prostate cancer [
increased the reliability of our result that UBE2C exerted
an oncogenic influence on breast cancer cells. There was
also a difference between UBE2C expression in different
molecular subtypes of breast cancer, among which the
positive rate of UBE2C expression in
HER2-overexpression BRCA was the highest, while the positive expression
rate of UBE2C was the lowest in Luminal A BRCA. In
the analysis of the relationship between UBE2C
expression and other common biomarkers for BRCA, UBE2C
expression was positively correlated with the expression
of P53, HER2 and Ki-67. Conversely, UBE2C expression
was negatively correlated with ER and PR expression.
Research conducted by Pan et al. confirmed the
overexpression of UBE2C in BRCA tissues as well as the
significant correlation between UBE2C expression and the
degree of cell differentiation, molecular types, and Ki-67
or HER2 expression . Similarly, Berlingier et al. also
reported that the expression of UBE2C in BRCA tissues
was significantly higher than that in normal breast
tissues, and UBE2C expression was positively correlated
with Ki-67 and HER2 expression (P < 0.05) [
agreed with our results. With regard to the prognostic
value of UBE2C expression in BRCA, a study from Psyrri
et al. demonstrated that BRCA patients with high UBE2C
mRNA expression experienced worse overall survival
]. Furthermore, a Cox multivariate regression
analysis from the study of Psyrri et al. suggested that UBE2C
mRNA expression was an independent prognostic
factor for BRCA patients [
], which was in accordance
with the results from the Kaplan–Meier survival analysis
for BRCA patients with different UBE2C expression in
Oncolnc. Nevertheless, the Kaplan–Meier survival
analysis and multivariate Cox hazard regression analysis in our
study from IHC data yielded contradictory results that
there was no statistically significant difference between
UBE2C expression and the survival of BRCA patients.
We considered that the limited patient samples and short
follow-up time might contribute to the contradictory
results. There were only eight patients that died during
the follow-up time before April 16, 2016, which might
have had a significant impact on the results. Further
studies with larger patient cohorts and longer follow-up
time were necessary to assess the prognostic significance
of UBE2C on survival of BRCA patients.
Apart from the IHC data, UBE2C gene expression
data from public databases including the HPA database,
Oncomine and Firebrowse provided a consistent result
showing UBE2C overexpression in BRCA tissues, which
supported the IHC results. Specifically, we demonstrated
an increasing significance in the difference between
UBE2C expression in BRCA tissues and normal tissues
with the enhanced malignancy of the same type of BRCA
using data from the Oncomine database. We speculated
that UBE2C expression was indicative of the malignant
progression of BRCA. Moreover, the result that UBE2C
expression in ductal carcinoma was obviously higher
than most other types of breast cancer suggested that
UBE2C could be used as a potential marker for
distinguishing ductal carcinoma from other types of breast
To facilitate a comprehensive understanding of the
mechanism of UBE2C expression in BRCA, we
investigated gene alteration of UBE2C in BRCA with available
data from cBioPortal. From the BRCA cases with UBE2C
gene alteration, amplification and mRNA up-regulation
comprised the major types of gene alteration, which might
be triggered by the aberrant expression of upstream
molecules that moderate the expression of target mRNAs.
MicroRNA (miRNA), a short non-coding RNA 21–24
nucleotides in length that silences target mRNA expression
through complete or incomplete binding to the
3′-untranslated region (3′-UTR) of the target mRNAs [
], is an
typical example of a molecule that regulates downstream
mRNA expression. Recently, accumulating studies have
noted that miRNAs were engaged in a series of biological
processes including proliferation, diversification,
metastasis, and apoptosis in the development of cancer [
Several studies have also revealed that miRNAs interact
with UBE2C to affect the progression of cancers. In gastric
cancer, miRNA-17/20 promoted gastric cancer cell growth
via targeting UBE2C [
]. In BRCA, the study of Han et al.
identified UBE2C as a direct and functional target of
miR196a which can upregulate the expression of UBE2C [
Meanwhile, we obtained a list of miRNAs including
miR671, miR-615, miR-20a, miR-17 and miR-196a through
the gene-miRNA targets function of miRWalk 2.0, which
were predicted to regulate the expression of UBE2C. Thus,
we hypothesized that UBE2C might serve as a substrate
of specific miRNAs that stimulate the overexpression of
UBE2C and exert an oncogenic influence on BRCA. Future
studies were needed to investigate the role for microRNAs
in regulation of UBE2C expression. To trace the origins
of the UBE2C gene alteration, we explored the
interactions between UBE2C and the top 50 frequently altered
neighboring genes. From the gene network, some genes
such as ASB7, ARIH2, KLHL20, KLHL9, ASB13, HERC2
and MGRN1 can be seen to form a complex with UBE2C;
some other genes, including TRIM11, PSMD12, WWP2,
SMD3 and PSMD8, directly interact with UBE2C. We
hypothesized that the gene alteration of UBE2C might be
explained by the abnormal activities of these genes, and
these genes may also exert carcinogenic effects in BRCA
through cooperating with UBE2C. Further studies are
warranted to validate the interaction between UBE2C and
these genes in the tumorigenesis of BRCA.
In summary, overexpressed UBE2C plays a crucial role in
the occurrence and development of BRCA. The
clinicopathological significance of UBE2C in BRCA suggests the
possibility of using UBE2C as a worthwhile biomarker for
BRCA in clinical applications. However, future
experiments are necessary to unveil the molecular basis of
UBE2C expression in BRCA.
UBE2C: ubiquitin‑ conjugating enzyme E2C; BRCA: breast carcinoma; IHC:
immunohistochemistry; HPA: human protein atlas; TCGA: the cancer genome
atlas; PBS: phosphate buffer saline; ER: estrogen; PR: progesterone; UPP: ubiq‑
uitin–proteasome proteolytic; MiRNA: microRNA.
CHM: performed most of the experiments as well as statistical analysis and
supervised the progression of research. LG: analyzed and interpreted data and
drafted the manuscript. XFZ, KLW, JJZ, GC and ZBF: participated in sample
collection and provided information from database. All authors read and
approved the final manuscript.
The authors declare that they have no competing interests.
Availability of data and materials
The datasets generated and analysed during the current study are available in
the HPA database (http://www.proteinatlas.org/), Oncomine database (https://
www.oncomine.org/resource/login.html), Firebrowse (http://www.firebrowse.
org/viewGene.html?gene=UBE2C), Oncolnc (http://www.oncolnc.org/) and
Consent for publication
Ethics approval and consent to participate
The study protocol was approved by The Ethical Committee of First Affiliated
Hospital of Guangxi Medical University. All the patients signed the written
informed consents based on the guidelines of the First Affiliated Hospital of
Guangxi Medical University before participating in the study. All tissue sam‑
ples were made anonymous according to the ethical and legal standards.
This study was supported by Guangxi Natural Scientific Fund (2015GXNS‑
FAA139187) and the self‑funded research projects of Guangxi Zhuang
Autonomous Region health and Family Planning Commission (Z2016185). The
funding body had no contribution to the design of the study and collection,
analysis, and interpretation of data and in writing.
Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations.
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