Hindawi

Disease Markers
Volume 2020, Article ID 5327378, 6 pages
https://doi.org/10.1155/2020/5327378

Research Article
Serum Actinin-4 Levels as a Potential Diagnostic and Prognostic
Marker in Cervical Cancer

Xigui Ma,1 Huiying Xue,2 Jixiang Zhong,2 Bo Feng,2 and Yanghua Zuo 2

1
Department of Traditional Chinese Medicine, Huai’an Maternal and Child Health Care Hospital, Renmin South Road 104,
Huai’an 223002, China
2
Department of Reproductive Center, Huai’an Maternal and Child Health Care Hospital, Renmin South Road 104,
Huai’an 223002, China

Correspondence should be addressed to Yanghua Zuo; [email protected]

Received 15 October 2019; Revised 13 March 2020; Accepted 8 June 2020; Published 14 August 2020

Academic Editor: Kishore Chaudhry

Copyright © 2020 Xigui Ma et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. The present study was aimed at determining the serum levels of actinin-4 (ACTN4) in cervical cancer (CC) and
investigating the diagnostic and prognostic value of serum ACTN4 in CC. Materials and Methods. We included 93 CC patients,
52 cervical intraepithelial neoplasia (CIN) patients, and 70 healthy women. Serum ACTN4 levels were assessed using an ELISA
method. A receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic value of serum ACTN4. The
survival curves were used to display the overall survival distributions. Results. Serum ACTN4 levels in CC patients were 48:39 ±
13:98 pg/mL which is significantly higher than those in CIN patients (32:72 ± 9:44 pg/mL; P < 0:001) and those in healthy
controls (30:84 ± 8:08 pg/mL; P < 0:001). The ROC analysis demonstrated that the area under the curve (AUC) of ACTN4 was
0.852 (95%CI = 0:796 – 0:908), with sensitivity of 76.3% and specificity of 87.7%. Serum ACTN4 levels were associated with the
FIGO stage, lymph node metastasis, and lymphovascular space invasion of CC (all P < 0:05). The survival curve suggested that
high serum ACTN4 levels were related to poor prognosis. Conclusion. Our findings suggest that serum ACTN4 levels may be
valuable diagnostic and prognostic biomarkers for CC.

1. Introduction misleadingness in the choices of prevention measures and

treatment for CC [6]. Noteworthily, when applying the same
Cervical cancer (CC) is the second most common female treatment plan to patients with similar pathological types, the
malignancy globally, and it is the most common female efficacy and prognosis are quite different. Therefore, it is nec-
malignancy in developing countries which has high morbid- essary to identify new biomarkers directly related to the pro-
ity and mortality rates [1]. In recent years, the incidence of gression and prognosis of CC.
CC has increased greatly in young women under the age of Alpha-actinins (ACTNs) are actin-binding proteins in
35 [2]. Despite great advances in surgical and adjuvant ther- the spectrin gene superfamily [7], which are known to be
apy, the overall survival of CC patients, especially that of cross-linked with filamentous actin (F-actin) to maintain
advanced patients, is still very poor [3]. At present, a Pap the integrity of cytoskeleton and to control cell motility [8].
smear combined with an HPV test has been used for the early The ACTN family has four members, numbered ACTN1–4,
screening of cervical lesions. However, the screening which are present in humans and other mammals [9–11].
methods are invasive and costly, leading to lower screening ACTN4 is encoded by the ACTN4 gene and is widely
coverage in China [3]. Previous studies have reported that expressed in many tissues, especially in glomerular podocytes
the human papillomavirus (HPV) screening results have a [12]. ACTN4 has an actin-binding domain at the N-termi-
relatively high false-positive rate and a relatively low specific- nus, and ACTN4 monomers can form a homodimer through
ity [4, 5]. In addition, the results of TCT interpretation by reverse binding, forming a dumbbell-shaped structure [13].
film-reading doctors are uneven, which might cause some As an actin-binding protein, ACTN4 is closely related to
2 Disease Markers

enhancing cell viability and tumor invasion and metastasis to obtain the overall survival (OS) time of CC patients, and
[14]. Recent researches have reported that the expression of the OS was defined as the time from diagnosis to death or
ACTN4 is significantly elevated in multiple cancers, includ- the last follow-up. The follow-up was in accordance with
ing breast cancer [14], pancreatic cancer [15], ovarian cancer the FIGO guidelines.
[16], and lung cancer [17]. In addition, the ACTN4 levels are
markedly associated with the poor prognosis of lung cancer 2.3. Blood Sample Collection and Detection of Serum Actinin-
[18, 19], thyroid cancer [20], and salivary gland carcinoma 4 and SCCA. A 5 mL peripheral blood sample from each
[21]. An et al. [22] have found that the expression level of patient was collected before receiving any treatment. After
ACTN4 in human cervical tumors is dramatically higher standing at room temperature for 10 minutes, the blood sam-
than that in normal cervical tissues. Their finding demon- ples were centrifugated at 1,500 g/min for 15 min, and then,
strated that ACTN4 promotes the epithelial-to- the supernatant was stored at −80°C until further usage.
mesenchymal transition and tumorigenesis by regulating The serum actinin-4 concentration was measured by a quan-
Snail expression and the Akt pathway in CC [22]. Therefore, titative enzyme-linked immunosorbent assay (ELISA)
the expression of ACTN4 in cervical tissues may be used in method (Uscn Life Science Inc., Wuhan, China). The levels
the clinical diagnosis and prognosis prediction of CC. of SCCA in serum were determined using an ELISA kit
However, up to now, the significance of the serum (R&D Systems, Minneapolis, MN). The detection of all sam-
ACTN4 levels in CC has not been evaluated. Hence, in the ples was strictly in accordance with the instructions provided
current study, the serum levels of ACTN4 in patients with by the manufacturer and was performed in duplicates.
CC were measured. In addition, we estimated the potential
diagnostic and prognostic value of serum ACTN4 expression 2.4. Statistical Analysis. All statistical analyses were con-
in CC. ducted by using SPSS 23.0 and GraphPad Prism 8. The con-
tinuous data following normal distribution were expressed as
2. Materials and Methods the mean ± standard deviation ðSDÞ. A t-test was used to
compare serum ACTN4 levels between the two subgroups
2.1. Study Population. A retrospective study was designed to of each clinicopathological parameters, and the serum
evaluate serum actinin-4 as a biomarker for CC. Between July ACTN4 levels of CC patients, CIN patients, and healthy con-
2012 and June 2014, 93 newly diagnosed female CC patients trols were compared by the SNK-q test. Receiver operating
and 52 newly diagnosed female cervical intraepithelial neo- characteristic (ROC) curves were performed to assess the
plasia (CIN) patients who received treatment at Huai’an diagnostic value of serum ACTN4 levels for differentiating
Maternal and Child Health Care Hospital (Huai’an, Jiangsu, CC patients from CIN patients and healthy controls. The
China) were recruited. The diagnoses of all patients were ver- Kaplan-Meier method and log-rank test were used to plot
ified by the histopathological examination. The patients with survival curves. The Cox proportional hazards models in uni-
other types of tumor or autoimmune, atherosclerotic, and variate and multivariate analyses were used for evaluating the
hematologic diseases were excluded. The mean age of CC prognostic value of serum ACTN4 expression. A two-tailed P
patients was 47.3 years with a range of 26-78 years. Mean- value < 0.05 was considered to be statistically significant.
while, 70 healthy women with no evidence of neoplasms
and other serious diseases were enrolled from the physical 3. Results
examination center in the same hospital. There was no signif-
icant difference in age among the CC, CIN, and healthy con- 3.1. Serum ACTN4 Levels Are Higher in Patients with CC.
trol groups. This study was consistent with the Helsinki Serum concentrations of ACTN4 were detected to range
declaration and was authorized by the Ethics Committee of from 13.38 to 82.67 pg/mL with a mean (±SD) of 48:39 ±
Huai’an Maternal and Child Health Care Hospital (approval 13:98 pg/mL for CC patients, to range from 3.71 to
number: H20130504). All participants signed written 61.32 ng/mL with a mean (±SD) of 32:72 ± 9:44 pg/mL for
informed consent. CIN patients, and to range from 18.99 to 49.76 ng/mL with
a mean (±SD) of 30:84 ± 8:08 pg/mL for healthy controls.
2.2. Clinicopathologic Feature Collection and Follow-Up. By Serum ACTN4 levels in CC patients were significantly higher
reviewing the medical records, we collected the clinicopatho- than those in CIN patients and healthy controls (P < 0:001).
logic characteristics of the patients, including age at diagno- However, no significant difference in serum ACTN4 was
sis, pathological type, FIGO stage, tumor differentiation, found between CIN patients and healthy controls
pelvic lymph node metastasis, tumor size, and lymphovascu- (P = 0:607), as shown in Figure 1.
lar space invasion. The CC patients were classified based on
the revised FIGO staging system for CC in 2009. The tumor 3.2. The Diagnostic Value of Serum ACTN4 Levels for CC. We
size was the maximum tumor diameter determined by a next used ROC curve analysis to estimate the diagnostic value
gynecologic oncologist during pelvic examination. The of serum ACTN4 expression for CC. The ROC curve showed
patients in stage 1A1 received hysterectomy; the patients in that the serum levels of ACTN4 were robust for discriminat-
stages IB1 and IIB received radical hysterectomy and pelvic ing CC patients from benign and healthy control subjects,
lymph node dissection; the patients with ≥stage IIB received with an area under the curve (AUC) value of 0.852
radiotherapy or radiotherapy combined with chemotherapy. (95%CI = 0:796 – 0:908), as demonstrated in Figure 2.
A regular telephone follow-up was conducted after treatment According to maximum Youden’s index, we used
Disease Markers 3

⁎ lymph node metastasis were the independent prognostic fac-

100 tors for CC (all P < 0:05) (Table 2).
⁎

80 4. Discussion
n.s.
Cervical cancer is a heterogeneous disease with complicated
ACTN4 (pg/mL)

60 etiology. Genetic and environmental factors play a crucial

role in the pathogenesis of CC [23]. Although the diagnosis
and prognosis of CC have improved greatly over the past
40
few decades, it is necessary to improve early detection and
screening methods to determine additional promising circu-
20 lating biomarkers for better patient selection and more per-
sonalized treatments [24]. As far as we know, this study
represented the first effort to evaluate the serum expression
0 of ACTN4 as a new biomarker for CC.
CC CIN CON
As an actin-binding protein, ACTN4 can participate in
Figure 1: The serum ACTN4 levels in CC patients, CIN patients, regulating cell migration, invasion, and metastasis via regu-
and healthy controls. ∗ P < 0:001. lating the actin filament flexibility at the leading edge of
invading cancer cells [25, 26]. ACTN4-overexpressing cancer
cells have the potential to metastasize, because the overex-
40.62 pg/mL as the cutoff value, and the sensitivity and spec- pression of ACTN4 protein in cancer cells can stimulate the
ificity were 76.3% and 87.7%, respectively. dynamic reconstruction of the actin cytoskeleton [27]. Up
to now, numerous studies have reported the association
3.3. Association between Serum ACTN4 Levels and between ACTN4 and multiple cancers. Okamoto et al. [18]
Clinicopathological Parameters of CC Patients. We further observed that ACTN4 is expressed in small-cell lung cancer
investigated the correlations between serum levels of ACTN4 (NSCLC), and it had a significant correlation with invasion
and clinical pathological data of 93 CC patients, and the and distant metastasis. Additionally, ACTN4 was reported
results are demonstrated in Table 1. We observed that serum to be a potential predictive biomarker for the efficacy of adju-
ACTN4 levels were related to the FIGO stage, lymph node vant chemotherapy in patients with NSCLC [19]. Watabe
metastasis, and lymphovascular space invasion (all P < 0:05 et al. [21] revealed that the copy number increase of ACTN4
). Nevertheless, no significant association was found between is a novel indicator for poor overall survival of patients with
serum ACTN4 levels and age, pathological type, differentia- salivary gland carcinoma, and the copy number variation
tion degree, and tumor size in CC patients (all P > 0:05). would affect the expression of protein. A recent study dem-
onstrated that serum ACTN4 levels were dramatically ele-
3.4. Survival Analysis of Serum ACTN4 Levels in CC. During vated in patients with breast cancer when compared to
the follow-up period, nine CC patients were lost, and the healthy controls, and serum ACTN4 may be an effective clin-
followed up rate is 90.3%. Finally, the prognostic value of ical indicator for diagnosing or predicting the clinical out-
serum ACTN4 was assessed in 84 patients. The patients were comes of breast cancer patients [14]. In addition, ACTN4
followed up to December 2018. The range of follow-up time was proven to be associated with the pathogenesis of CC.
was 6 to 60 months, with the median time of 46.0 months and An et al. [22] proposed a novel mechanism for epithelial-
mean time of 43.2 months. According to the median serum to-mesenchymal transition and tumorigenesis in CC which
levels of ACTN4 in CC patients (47.50 pg/mL), the 84 CC could be induced by ACTN4 through regulating Snail expres-
patients were divided into the high ACTN4 level group sion and β-catenin stabilization. Hence, it is significant to
(<47.50 pg/mL, N = 42) and low ACTN4 level group investigate the role of serum ACTN4 in CC.
(≥47.50 pg/mL, N = 42). The estimated 5-year OS of patients In the current study, we observed that serum levels of
with high serum ACTN4 levels and low serum ACTN4 levels ACTN4 in CC patients were statistically higher than those
were 67.3% and 86.2%, respectively. The Kaplan-Meier sur- in CIN patients and those in healthy controls. However,
vival curve and log-rank test indicated that CC patients with serum ACTN4 levels were not significantly different between
high serum ACTN4 levels had a worse prognosis than those the CIN group and the control group. It was shown that
with low serum ACTN4 levels (P = 0:013) (Figure 3). serum ACTN4 expression could strongly differentiate CC
Univariate Cox regression analyses showed that the patients from CIN patients and healthy controls. The ROC
serum ACTN4 levels (P < 0:001), FIGO stage (P < 0:001), analysis demonstrated that the AUC of ACTN4 was 0.852,
differentiation degree (P = 0:012), lymph node metastasis and at the optimal cutoff of 40.62 pg/mL, the sensitivity and
(P < 0:001), and lymphovascular space invasion (P = 0:024) specificity were, respectively, 76.3% and 87.7%, suggesting
had significant prognostic value for OS. Multivariate analysis that serum ACTN4 might be a potential diagnostic bio-
was further performed to evaluate the prognostic value of marker for CC. In a recent study which included 800 Chinese
serum ACTN4 as an independent factor for CC. All the sta- women, Hu et al. [4] reported that the sensitivity and speci-
tistically significant factors from univariate analyses were ficity of HPV screening in the diagnosis of CC were 77.25%
included, and the results indicated that the FIGO stage and and 65.37%. The sensitivity of the HPV test was a litter higher
4 Disease Markers

1.0

0.8

0.6

Sensitivity

0.4

0.2

0.0
0.0 0.2 0.4 0.6 0.8 1.0
1 − specificity

Figure 2: ROC curve analysis assessed the diagnostic performance of serum ACTN4 in CC. The AUC was 0.852, P < 0:001.

Table 1: Serum ACTN4 levels in CC patients according to than that of serum ACTN4 detection, though the specificity
clinicopathological parameters. of serum ACTN4 detection was well above that of the HPV
test. Hence, comparing with the HPV test in diagnosing
ACTN4
Parameters N % P CC, detecting serum ACTN4 has some advantages. Further-
(pg/mL)
more, serum ACTN4 levels have been indicated to be a great
Age (years) biomarker for diagnosing multiple cancers. Fang et al. [14] in
≤45 39 41.9 49:30 ± 12:36 0.491 their study reported that serum ACTN4 was a promising
>45 54 58.1 47:36 ± 13:93 indicator for diagnosing breast cancer, with the AUC of
Pathological type
0.887. Wang et al. [17] used ACTN4 expression in peripheral
blood to differentiate NSCLC patients from healthy individ-
Squamous cell carcinoma 72 77.4 47:66 ± 13:62 0.434 uals in two groups of participants, and they obtained both
Adenocarcinoma 21 22.6 49:94 ± 12:07 satisfactory effects. Furthermore, we investigated the correla-
FIGO stage tion between serum ACTN4 and clinical characteristics of
IA1-IB1 52 55.9 45:31 ± 12:67 0.017 CC patients. The serum ACTN4 levels were significantly
associated with the FIGO stage, lymph node metastasis, and
≥IB2 41 44.1 52:29 ± 14:83
lymphovascular space invasion of CC, which suggests that
Differentiation ACTN4 could contribute to the development, invasion, and
Well and moderately metastasis of CC. In addition, our results indicated that high
63 67.7 47:38 ± 12:94 0.209
differentiated ACTN4 levels were associated with the poor survival of CC
Poorly differentiated 30 32.3 50:65 ± 13:78 patients. In the multivariate analysis, although ACTN4 levels
Lymph node involvement did not reach the statistical significance, it still seems to be
able to influence the OS.
Negative 66 71.0 43:65 ± 13:54 <0.001
However, several limitations in the present study should be
Positive 27 29.0 59:97 ± 16:23 taken into consideration. First, the sample size was relatively
Tumor size small, which was likely to reduce the statistical power of our
≤2 59 63.4 49:29 ± 12:67 0.284 results. Second, we only explored the relationship between
>2 34 36.6 46:17 ± 14:19
serum ACTN4 and OS, and other prognostic indicators were
not examined due to the incomplete data, which needs to be
Lymphovascular space invasion improved in the future. Third, this study was a primary study
Negative 58 62.3 44:21 ± 10:96 <0.001 to determine the clinical significance of serum ACTN4 levels
Positive 35 37.6 55:64 ± 16:32 for the diagnosis and prognosis of CC, but the specific molecu-
lar mechanisms remain unclear. Hence, further experiments
should be conducted to elucidate the mechanisms.
In conclusion, our study showed that serum ACTN4
levels were increased in CC patients and were related to the
Disease Markers 5

100

Cum survival (%)

50

Log rank P = 0.013

0
0 20 40 60
Overall survival (months)
Low ACTN4 group
High ACTN4 group

Figure 3: Kaplan-Meier curve compared OS of CC patients with high serum ACTN4 levels versus those with low serum ACTN4 levels.

Table 2: Univariate and multivariate Cox regression analysis of OS in CC patients.

Univariate Multivariate
Variables
HR 95% CI P HR 95% CI P
Age (>45 vs. ≤45 years) 1.331 0.712–2.372 0.643 —
Pathological type (squamous cell carcinoma vs. adenocarcinoma) 1.106 0.903–1.341 0.874 —
FIGO stage (≥IB2 vs. IA1-IB1) 2.818 1.746–4.112 <0.001 2.015 1.464–3.046 0.017
Differentiation (poorly differentiated vs. well and moderately differentiated) 1.874 1.412–3.648 0.012 1.593 1.198–2.749 0.156
Lymph node involvement (positive vs. negative) 4.621 2.815–7.492 <0.001 2.907 1.315–7.124 <0.001
Tumor size (>2 vs. ≤2 cm) 1.536 1.115–2.896 0.257 —
Lymphovascular space invasion (positive vs. negative) 2.172 1.721–3.824 0.024 1.514 1.139–2.472 0.297
Serum ACTN4 levels (high vs. low levels) 2.442 1.806–4.113 <0.001 1.785 1.406–3.127 0.082

FIGO stage, lymph node metastasis, and lymphovascular Acknowledgments

space invasion of CC patients. In addition, serum levels of
ACTN4 have great diagnostic and prognostic value in CC. We thank all the patients and blood donors who participated
Nevertheless, further studies with a larger sample size should in our study. This study was funded by grants from the Sci-
be carried out to confirm our results. ence and Technology Project of Traditional Chinese Medi-
cine Bureau of Jiangsu province, China (YB2015128).

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