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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 9  |  Page : 444-449

Study on early diagnosis of epithelial ovarian cancer by analysis of plasma septin-9 and clusterin level


1 Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
2 Department of Gynecologic Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
3 Department of Biotechnology, Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China

Date of Web Publication29-Jun-2018

Correspondence Address:
Weimin Kong
Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.181178

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 > Abstract 

Background and Aim: To investigate the value of peripheral blood plasma levels of septin-9 and clusterin protein in the diagnosis of epithelial ovarian cancer (EOC).
Materials and Methods: The peripheral blood plasma samples were obtained from 137 EOC patients, 12 borderline ovarian tumor patients, 10 benign ovarian tumor patients, 41 benign pelvic lesion patients, and 58 healthy women. The peripheral plasma septin-9 and clusterin proteins levels were measured by enzyme-linked immunosorbent assay. The power of test was evaluated with the area under the receiver operating characteristic curve (ROC) (AUC).
Results: The mean levels of plasma septin-9 and clusterin in EOC patients were significantly higher than that in healthy women (P = 0.002, P = 0.021). The mean levels of plasma septin-9 in benign pelvic lesion patients were significantly higher than that in healthy women (P = 0.007). The mean levels of plasma septin-9 in epithelial ovarian carcinoma patients with tumor family history or distant metastases were significantly higher than that of patients without (P = 0.040, P = 0.025). The AUC of septin-9 protein was 0.712, when the optimal cut-off point was 0.28, the sensitivity and diagnostic specificity were 82.5% and 50.0%, respectively; the AUC of clusterin was 0.636, and when the optimal cut-off point was 87.96 ng/ml, the sensitivity and diagnostic specificity was 71.5% and 41.4%, respectively.
Conclusion: The plasma levels of septin-9 and clusterin in ovarian cancer patients were abnormally elevated, which might be used as potential candidates of peripheral blood tumor biomarkers for early diagnosis of EOC and septin-9 might be related to distal metastases of EOC. The septin-9 might play the promotion role, which protein level relates to not only the distal metastases but also the prognosis of EOC. Due to the limit of sample volume, further enlargement of the sample size and set up of the follow-up system is in need to in-depth study the relationship between plasma protein concentration with the distal metastases, and further explore its correlation with the prognosis of EOC.

Keywords: Clusterin, enzyme-linked immunosorbent assay, ovarian epithelial cancer, septin-9


How to cite this article:
Lyu N, Wang Y, Wang J, Zhang Z, Kong W. Study on early diagnosis of epithelial ovarian cancer by analysis of plasma septin-9 and clusterin level. J Can Res Ther 2018;14, Suppl S2:444-9

How to cite this URL:
Lyu N, Wang Y, Wang J, Zhang Z, Kong W. Study on early diagnosis of epithelial ovarian cancer by analysis of plasma septin-9 and clusterin level. J Can Res Ther [serial online] 2018 [cited 2019 Jul 17];14:444-9. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/444/181178


 > Introduction Top


Ovarian malignant tumors account for the highest mortality of female reproductive system tumors.[1] The pathologic type of 85–90% primary ovarian malignant tumors is epithelial ovarian cancer (EOC). More than 2/3 of patients may progress to the later period,[2] when they are diagnosed as EOC. The advanced stage EOC normally has very poor prognosis and only 23% of ovarian cancers are diagnosed as Stage I [3],[4] so that it is very crucial to fundamentally increase the 5-year survival rate and find out a novel effective epithelial ovarian tumor biomarker spectrum for early diagnosis.

Previously, while setting up the EOC-associated free protein database, we found out that septin-9 and clusterin existing as free protein in microenvironment of EOC tissue have certain relationship with the pathogenesis and development of malignant tumor, and further preliminarily explored on the protein level and the clinical significance of clusterin in the peripheral blood plasma of EOC patients, but whether these two proteins can be used as diagnostic biomarker has not been reported yet. Using enzyme-linked immunosorbent assay (ELISA) technique, this experiment performed detection and analysis of septin-9 and clusterin protein levels in the peripheral blood plasma of the EOC patients and the healthy control individuals and explored the possibility and the clinical significance of septin-9 and clusterin as the molecular biomarker for early diagnosis of EOC.


 > Materials and Methods Top


Study subjects

Plasma samples

Between January 29, 2008 and February 01, 2010, 258 peripheral blood plasma samples were randomly obtained from the EOC biological specimen banks set up by a cancer hospital and institute of China, including 137 EOC patients, 12 borderline ovarian tumor patients (borderline serous cystadenoma/mucinous cystadenoma), 10 benign ovarian tumor patients (serous cystadenoma/mucinous cystadenoma), 41 benign pelvic lesion patients (ovarian endometrial cyst and pelvic inflammatory encapsulated effusion), and 58 healthy women of same age. All patients were originally diagnosed in Beijing Chao-Yang Hospital, Capital Medical University, and Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Among above 137 EOC patients, the mean age was 56 years old (18–80 years old). According to the Union for International Cancer Control 2009, all the ovarian cancer patients were performed clinical staging, including Stage I 14 cases (10.2%), Stage II 15 cases (10.9%), Stage III 88 cases (64.2%), Stage IV 14 cases (10.2%), and no clear stage 6 cases (4.4%). According to the standard of 1993 World Health Organization ovarian cancer histological staging and cell differentiation, there were serous cystadenoma 104 cases (75.9%), nonserous cystadenoma 33 cases (24.1%), high differentiation 6 cases (4.4%), middle differentiation 14 cases (10.2%), low differentiation and no differentiation 91 cases (66.4%) and no clear differentiation 26 cases (19.0%). In EOC patients, there were lymphatic metastases 39 cases (28.5%) and distal metastases 54 cases (39.4%) [Table 1]. This study was approved by the Internal Review Board of Cancer Hospital and Institute, Chinese Academy of Medical Sciences. Written informed consent was obtained from all patients.
Table 1: Clinical data of plasma samples

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Collection and preservation of the plasma samples

The venous blood samples were drawn with ethylene diamine tetra acetic acid anticoagulant tubes from the fasting patients in the morning, which were preserved at 4°C and sent to the laboratory 2 h later. After low-temperature centrifuge (1500 g, 4°C, 10 min), the upper layer plasma was preserved at −80°C for detection. Sample collection had got informed consent from the patients.

Detection of peripheral blood plasma level of septin-9 and clusterin protein by enzyme-linked immunosorbent assay

Detection of plasma level of septin-9 protein was used double antibody sandwich method. Detection of plasma level of clusterin protein was performed with ELISA kit [Table 2].
Table 2: Septin-9 protein level detection system

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Double antibody sandwitch method ELISA and ELISA were respectively used to detect the plasma protein level of septin 9 and clusterin: The detection of plasma septin-9 level was used double antibody sandwitch method ELISA. The capture antibody was the product of Beijing Aviva Systems Biology, the detection antibody was purchased from Abnova, Taiwan Province, China, and the HRP-labeled Streptavidin was the product of Dako Company, Denmark. The detection of plasma clusterin level was used ELISA. The ELISA detection kit was bought from BioVendor Company, Czech Republic. The detail procedure was occording to the instruction of the kit. The samples were put on the ELISA (Bio-Rad company, USA) and the OD450nm was read on the ELISA. OD value was performed statistical analysis using SPSS 18.0 software (SPSS, Inc., USA).

Statistic method

SPSS 18.0 (SPSS, Inc., USA) software was used to perform statistical analysis, and all statistical tests were two-sided, and a P < 0.05 was considered to be statistically significant. Comparison of the measurement data between two groups was used independent-samples t-test, and comparison between three groups and above was used one-way analysis of variance. Comparison between groups was used row × column Chi-square test. GraphPad Prism 5 (GraphPad Software Inc., USA) was used to plot the scatter diagram. The power of test was evaluated with the area under the receiver operating characteristic (ROC) curve (AUC).


 > Results Top


Analysis of peripheral blood plasma septin-9 and clusterin protein contents of each group

Through detection of peripheral blood plasma levels of septin-9 and clusterin of each group, it was found that the peripheral blood plasma levels of septin-9 and clusterin protein were increased than that of the control group, which difference was statistically significant, with P value being 0.002 and 0.021, respectively [Table 3] and [Figure 1]; the peripheral blood plasma levels of septin-9 in the pelvic benign disease group (endometriosis and pelvic inflammatory lesion) elevated than that in the healthy control group withstatistical significance, and P = 0.007.
Table 3: The peripheral blood plasma levels of septin-9 and clusterin protein in different patients groups and control groups

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Figure 1: Distribution of plasma levels of septin-9 and clusterin in every patient's group and healthy women group (a) Distribution diagram of plasma levels of septin-9; (b) Distribution diagram of plasma levels of clusterin

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Analysis of the relationship between the peripheral blood plasma levels of the two proteins with the age, smoking history, tumor family history, and treatment history (operation, chemotherapy, and radiotherapy) of the epithelial ovarian cancer patients

Through analysis of the relationship of the plasma levels septin-9 and clusterin protein with the age, smoking history, tumor family history, and treatment history (operation, chemotherapy, and radiotherapy) of the EOC patients [Table 4], we found that the peripheral plasma levels of septin-9 protein of the patients with tumor history was higher than that of patients without [Figure 2], and the difference was statistically significant, but the difference of other groups had no statistical significance.
Table 4: Analysis of the relationship of peripheral blood plasma levels of septin-9 and clusterin protein of ovarian cancer patients with its clinical and pathological factors

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Figure 2: Distribution of peripheral blood plasma levels of septin-9 in epithelial ovarian cancer patients with or without tumor family history. *Family = 0, without tumor family history; family = 1, with tumor family history

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Analysis of the relationship between the plasma levels of the two proteins and the clinical staging, tumor cell differentiation, lymph nodes metastases, and distal metastases of the epithelial ovarian cancer patients

To further analysis of the relationship of the levels plasma septin-9 and clusterin protein with the clinical staging, tumor cell differentiation, lymph nodes metastases, and distal metastases of the EOC patients, the peripheral blood plasma levels of septin-9 protein in the group with distal metastases was higher than in the group without [Figure 3], and the difference was statistically significance (P = 0.025). There was no statistical significance of septin-9 and clusterin levels between the Stage I + II and Stage III + IV (P = 0.256, P = 0.378); There was no statistical significance of plasma levels of septin-9 and clusterin protein between high differentiation, moderate differentiation, low differentiation, and no differentiation group (P = 0.359, P = 0.080); There was no statistical significance of peripheral blood plasma septin-9 and clusterin levels between lymph nodes metastases group and no lymph nodes metastases group.
Figure 3: Distribution of plasma levels of septin-9 in epithelial ovarian cancer patients with or without distant metastases. *Distal metastases = 0, without distal metastases; distance = 1, with distal metastases

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Power of test of septin-9 and clusterin

The AUC was used to evaluate the power of the test of septin-9 and clusterin. When the peripheral blood plasma levels of septin-9 and clusterin protein were used to distinguish the EOC patients and the healthy checkup individuals, the AUC of septin-9 protein was 0.712, and while the optimal cut-off point was 0.28, the sensitivity and diagnostic specificity was 82.5% and 50.0%, respectively; the AUC of clusterin was 0.636, and while the optimal cut-off point was 87.96 ng/ml, the sensitivity and diagnostic specificity were 71.5% and 41.4%, respectively [Table 5] and [Figure 4].
Table 5: The area under the receiver operating characteristic curve distinguishing between ovarian cancer group and healthy group according to the levels of septin-9 and clusterin protein

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Figure 4: Receiver operating characteristic distinguishing between ovarian cancer group and healthy group according to protein levels of septin-9 and clusterin. Note: When the sensitivity is 80.0%, the curves from left to right represent the reference line of septin-9 and clusterin, respectively

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 > Discussion Top


Septin-9 protein is coded by SEPT9 gene, locating in chromosome 17q25.3, which sector is the most common loss of heterozygosity site of sporadic EOC and breast cancer. The newest studies support that the SEPT9 is potential proto-oncogene.[5],[6] In the breast cancer caused by overexpression of PyV-mT, it is found that there is gene amplification of 17q25.3 region and upregulation of SEPT9 gene.[5]Thsp-1 and Bax may down-regulate in the breast cancer cell line with SEPT9 upregulation, and the cell apoptosis will be inhibited. After the small interfering RNA inhibit the expression of SEPT9, the inhibition of cell apoptosis will be removed.

The analysis result of Affymetrix HG_U133 gene microarray detection in 7287 fresh human tissues and 292 human cell lines showed the high expression of SEPT9 in breast, central nervous system, endometrium, kidney, liver, lung, lymph, esophagus, ovary, pancreas, soft tissue, skin, and thyroid origin tumors,[6] and which was consistent with the result of realtime polymerase chain reaction and immunohistochemical staining. The newest in vivo and in vitro experiments of prostate cancer cell line found that through inhibition of the ubiquitination degradation pathway of hypoxia-inducible factor-1 alpha (HIF-1α), MSF-A (SEPT9-vla) could promote the expression of HIF-1α and the tumor angiopoiesis.[7] The newest research indicates that septin-9 protein can play its role in the diagnosis of early period of lung cancer that has no metastases.[8] Some studies also had proven the upregulation of septin-9 in the tissue and plasma of the colon intraepithelial neoplasia patients.[9] The domestic authors also reported that methylation of SEPT9 could be taken as the early stage biomarker in the diagnosis of colon carcinoma patients.[10],[11]

Clusterin protein is coded by humanclusterin gene, positioning in 8p21-p12[12],[13] and involving in multi important physiological function including the interaction of cell-cell and cell-extracellular matrix, inflammation, cell movement, a molecular chaperone, cell oxidative stress, cell proliferation, cell apoptosis, and other functions.[15],[16],[17],[18] It is considered in recent years that except for exerting the function of increasing the stability of oxidative protein as an extracellular molecular chaperon, this protein is also an apoptosis-related protein involving the process of programmed cell death. Therefore, the relationship between the clusterin expression level and the tumor has attracted more and more attention. It is currently found by the domestic and aboard studies that that the abnormal expression is correlated with the tumorigenesis and development of multi tumors. Clusterin downregulates in esophageal squamous cancer and testicular seminoma cell carcinoma,[19],[20] and upregulates in bladder cancer, breast cancer, colorectal cancer.[14],[21],[22]

The previous research of this study showed that the septin-9 and clusterin are identified in the conditioned medium of EOC primary culture medium, indicating that the protein levels might increase in the peripheral blood plasma of EOC, and further study found the significantly increased level of clusterin protein in EOC. The current studies mostly concentrate on the analysis of the septin-9 and clusterin gene and protein expression at the tissue level of EOC,[23],[24] and whether these two proteins can be taken as the early diagnosis criteria has not been reported yet. This experiment underwent the detection and analysis of the two proteins in the peripheral blood plasma of the EOC patients and healthy control individuals and investigated the possibility and clinical significance of the septin-9 and clusterin as the plasma biomarker in the EOC.

The result showed that the peripheral blood plasma levels of septin-9 and clusterin in EOC patients were significantly higher than that in healthy women; when the peripheral blood plasma levels of septin-9 and clusterin were used to distinguish the EOC patients, and the healthy checkup individuals, the AUC of septin-9 protein was 0.712, and while the optimal cut-off point was 0.28, the sensitivity and diagnostic specificity was 82.5% and 50.0%, respectively; the AUC of clusterin was 0.636, and while the optimal cut-off point was 87.96 ng/ml, the sensitivity and diagnostic specificity were 71.5% and 41.4%, respectively.

Currently, the most common evaluation indexes of the veracity of diagnosis test are sensitivity and specificity. In recent years, the ROC curve has gradually been regarded as the optimal comprehensive index in the veracity of diagnosis test. ROC curve can synthesize the true positive rate and false positive rate at different critical point, and which is plotted with the true positive rate as the vertical rate and the false positive rate as the horizontal axis, and can estimate the diagnose rate of the diagnostic test through calculating the area under the curve, that is AUC.

AUC indicates the overlap degree of the distribution of positive and negative diagnostic results with the golden criteria of diagnosis, reflecting the value of the diagnostic test, and evaluating the relative accuracy of different diagnostic test. Theoretically, the value range of this index is 0.5–1.0, with totally no value diagnosis as 0.85 and perfect value diagnosis as 1. It is generally acknowledged that the AUC of ROC at 0.50–0.70 indicate the diagnostic accuracy be relatively low, at 0.70–0.90 mean the diagnostic accuracy being moderate and above 0.90 mean the diagnostic accuracy being relatively high. In this study, AUC of ROC was used to evaluate the power of diagnostic test of EOC. AUC of ROC of septin-9 and clusterin was respectively 0.712 and 0.636, both more than 0.5, indicating that detection of septin-9 and clusterin all be conductive to the diagnosis of epithelial cancer, especially the septin-9 being more significant. Therefore, the results of this study all indicated that these two proteins could be taken as the potential plasma biomarker of EOC. Studies also showed that the peripheral blood plasma septin-9 of benign pelvic disease group (mainly the pelvic ovarian endometrial cyst and pelvic inflammatory encapsulated effusion) was also significantly higher than that of the healthy control group, which might due to the interaction of septin-9 in the pathogenic microorganism infection. The result of this study showed that the peripheral blood plasma septin-9 of the EOC does not relate to the age, smoking history, treatment history, clinical staging, tumor cell differentiation, and lymph nodes metastases of the patients, but relates to the tumor family history, which indicates that further enlarged samples might find out the interaction between the septin-9 and clinical pathology factors of EOC and provide clinical clue of the function of septin-9 in the tumorigenesis and development of EOC.

When the epithelial patients had distal metastases, the peripheral blood plasma level of septin-9 significantly increased, indicating that the septin-9 might play the promotion role, which protein level relates to not only the distal metastases but also the prognosis of the EOC. Due to the limit of sample volume, further enlargement of the sample size and set up of the follow-up system is in need to indepth study the relationship between plasma protein concentration with the distal metastases, and further explore its correlation with the prognosis of the EOC.

Acknowledgments

The authors had full responsibility for the design of the study, the collection of the data, the analysis and interpretation of the data, the decision to submit the manuscript for publication, and the writing of the manuscript.

We thank Dr. Ting Xiao (Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, Cancer Hospital and Institute, Peking Union Medical College and Chinese Academy of Medical Sciences) for kindly providing the antibody and ELISA kit, Dr. Lingying Wu (Department of Gynecologic Oncology, Cancer Hospital and Institute, Peking Union Medical College and Chinese Academy of Medical Sciences) for assistance with statistical analyses.

Financial support and sponsorship

Basic and Clinic Scientific Research Cooperation Project (13JL20, 13JL69); Hospital Project of Beijing Obstetrics and Gynecology Hospital, Capital Medical University (201208).

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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