Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 11  |  Issue : 2  |  Page : 375-380

Clinical significance of plasma lysophosphatidic acid levels in the differential diagnosis of ovarian cancer


Department of Radiation Oncology Division, The First Hospital of Qinhuangdao City, Qinhuangdao, China

Date of Web Publication7-Jul-2015

Correspondence Address:
Yun-Jie Zhang
Department of Radiation Oncology Division, The First Hospital of Qinhuangdao City, Cultural Road No. 258, Qinhuangdao-066 000
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.157335

Rights and Permissions
 > Abstract 

Objective: To investigate the value of lysophosphatidic acid (LPA) in the diagnosis of ovarian cancer.
Materials and Methods: We first performed a hospital-based, case-control study involving 123 ovarian cancer patients and 101 benign ovarian tumor patients, and then conducted a meta-analysis with 19 case-control studies to assess the correlation between ovarian cancer and plasma LPA levels.
Results: The case-control study results demonstrated that ovarian cancer patients have increased LPA and cancer antigen (CA)-125 levels compared to patients with benign ovarian tumor (LPA: Ovarian cancer vs benign ovarian tumor: 5.28 ± 1.52 vs 1.82 ± 0.77 μmol/L; CA-125: Ovarian cancer vs benign ovarian tumor: 87.17 ± 45.81 vs. 14.03 ± 10.14 U/mL), which showed statistically significant differences (both P < 0.05). LPA with advanced sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate of diagnosis excelled CA-125 in the diagnosis of ovarian cancer (both P < 0.05). The areas under the receiver operating characteristic (ROC) curve in the diagnosis of ovarian cancer (LPA: 0.983; CA-125: 0.910) were statistically significant compared with the reference (both P < 0.001) and the difference of the areas of ROC curve between LPA and CA-125 in the diagnosis of ovarian cancer showed statistically significant difference (P < 0.05). The meta-analysis results suggested that plasma LPA levels were higher in ovarian cancer tissues than in benign tissues (standardized mean difference (SMD) =2.36, 95% confidence interval (CI): 1.61-3.11, P < 0.001) and normal tissues (SMD = 2.32, 95% CI: 1.77-2.87, P < 0.001).
Conclusion: LPA shows greater value in the diagnosis of ovarian cancer compared to CA-125 and may be employed as a biological index to diagnose ovarian cancer.

Keywords: Benign ovarian tumor, bioactive phospholipid, CA-125, diagnosis, endothelial differentiation gene, G protein-coupled receptors, lysophosphatidic acid, ovarian cancer, sensitivity, specificity


How to cite this article:
Zhang YJ, Cao LY, Fu ZZ, Wang YJ, Wang GX, Gu T. Clinical significance of plasma lysophosphatidic acid levels in the differential diagnosis of ovarian cancer. J Can Res Ther 2015;11:375-80

How to cite this URL:
Zhang YJ, Cao LY, Fu ZZ, Wang YJ, Wang GX, Gu T. Clinical significance of plasma lysophosphatidic acid levels in the differential diagnosis of ovarian cancer. J Can Res Ther [serial online] 2015 [cited 2019 Aug 21];11:375-80. Available from: http://www.cancerjournal.net/text.asp?2015/11/2/375/157335


 > Introduction Top


Ovarian cancer is the second most common lethal cancer among gynecologic tumors originally in that the highly metastatic cells slough from primary tumors and subsequently spread throughout the peritoneal cavity. [1] Ovarian cancer represents the fifth leading causes of malignancy-related mortality among women in the United States with approximate 15,000 deaths each year. [2],[3] The risk of ovarian cancer enhances in individuals who have greater lifetime ovulations, and thus those who have never had children are at high risk. [4] Besides, low parity, early age of menarche, late age of menopause, excessive gonadotropin secretion, transportation of carcinogens, and lifestyle (smoking or obesity) appears to be involved with the onset and development of ovarian cancer. [5],[6] Due to lack of specific symptoms presented by ovarian cancer and no screening techniques recommended to diagnose preinvasive or early-stage disease, more than 70% of patients are diagnosed at advanced stage and the prognosis in advanced-stage ovarian cancer remains poor with a 5-year survival rate of less than 30%. [7],[8] Currently, cancer antigen (CA)-125 has been still extensively used to diagnose ovarian cancer, while it does not show great value in the diagnosis of ovarian cancer with relatively dissatisfactory sensitivity and specificity. [9]

Lysophosphatidic acid (LPA) is a water-soluble phospholipid that comprises a phosphate, a glycerol, and a fatty acid and can be served as a potent signaling molecule. [10],[11] LPA in blood is produced from extracellular lysophosphatidylcholine by a secreted lysophospholipase D, called autotaxin, primarily isolated as an "autocrine motility factor" for tumor cells. [12] To date, at least six specific G protein-coupled receptors have been identified, termed LPA receptor-1 (LPA1), LPA2, LPA3, LPA4, LPA5, and LPA6, which mediate both distinct and overlapping signaling pathways. [13],[14] Through the binding of G protein-coupled LPA receptors, LPA facilitates a wide range of biological functions, such as cell proliferation, differentiation, migration, cytoskeleton reorganization, cytokine production, platelet aggregation, morphogenesis changes, and cell survival both normal and malignant. [15] Under normal circumstances, LPA in the body fluids and bloodstream is at submicromolar concentrations or lower; but in ascites fluid of ovarian cancer patients, it seems to have higher concentrations. [16]

Many studies have assessed the correlation between LPA and ovarian cancer. [17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35] Nevertheless, the results from these underpowered studies have failed to clearly and reliably resolve this question. Therefore, we have performed a new case-control study with larger sample size to investigate LPA and ovarian cancer, and then combined our results with a meta-analysis of related studies to obtain a more definitive and precise estimate of LPA-ovarian cancer correlation.


 > Materials and methods Top


Ethical statement

The study was approved by the Ethics Committee of the Second Hospital of Jilin University, China. All eligible patients signed a document of informed consent, and this study was performed based on the Declaration of Helsinki. [36]

Subjects

This cases-control study enrolled 123 ovarian cancer patients aged 29-65 years (median age 55 years) and 101 benign ovarian tumor patients aged 28-66 years (median age 54 years) between January 2013 and September 2014 form the first hospital of Qinhuangdao City. The pathological types are: Serous cystadenocarcinoma (n = 66), mucinous cystadenocarcinoma (n = 16), and endometrioid carcinoma (n = 13). Pathological staging based on the International Federation of Gynecology and Obstetrics (FIGO) in 2014: [37] Fourteen in stage I, 16 in stage II, 62 in stage III, and eight in stage IV. All subjects were undertaken pathological diagnosis and patients with other gynecologic tumors, pelvic inflammatory disease, vascular occlusive diseases, hypertension, and diabetes mellitus were excluded.

Determination of LPA and CA-125 levels

All subjects with empty stomachs were peripherally phlebotomized at 6 ml, which was anticoagulated by the anticoagulant (No. 1; Beijing Taifushi Technical Developing Company) present in the LPA kit for the determination of LPA and CA-125. After centrifugation at 8,000 rpm for 10 min, the supernatant (1 ml) was absorbed, sample was extracted for phospholipid, chromogenic agent was added and kept in water bath at 90°C for 5 min, and then maintained at room temperature for 35 min. The semiautomatic biochemical analyzer (BG2000B) was used for colorimetry and absorbance (A) at the wavelength of 636mm (LPA = 30 × ((A sample - A control )/(A sample - A control ))). All subjects in two groups with empty stomachs were peripherally phlebotomized at 3 ml again in which CA-125 was determined by radioimmunoassay. The critical values of normal plasma LPA and CA-125 levels are 1.3 μmol/L and 35 U/mL, respectively. [35],[38]

Statistical analysis

Statistical Package for Social Sciences (SPSS) 20.0 was employed for our statistical analysis. Continuous data were exhibited by standard deviation ± mean using t-test for further examination; while categorical data were presented with percentage using Chi-square test. P < 0.05 was defined as significant.

Meta-analysis

An electronic search was undertaken in the following databases: PubMed, Wanfang, China National Knowledge Infrastructure (CNKI), and VIP (updated on May 30 th , 2014) for published papers investigating the correlation of plasma LPA levels with ovarian cancer, utilizing relevant keywords ("lysophosphatidic acid" or "MOPA" or "LPA" or "1-oleoyl-lysophosphatidic acid" or "monooleylphosphatidate" or "1-O-oleyllysophosphatidic acid") and ("ovarian tumors" or "ovary tumors" or "ovary cancers" or "ovarian cancer" or "cancer of ovary" or "ovarian carcinoma" or "ovarian adenocarcinoma" or "ovarian tumor" or "EOC"). Our meta-analysis enrolled human-associated case-control studies that focused on the diagnostic value of plasma LPA levels in ovarian cancer. Subsequently, we excluded abstract, summary, duplicates, or studies without control population. During the process of statistical analysis, the summary standardized mean differences (SMDs) with 95% confidence interval (CI) were calculated to provide quantitative evidence of all included studies by a random-effects model or a fixed-effects model. [39] A random-effect model was employed when the heterogeneity exists among studies; otherwise a fixed-effect model was applied. The Cochran's Q-statistic (P < 0.05 was defined as statistically significant) was available for the evaluation of the heterogeneity [40] which was further examined by I2 test (0 ~ 100%: No heterogeneity ~ maximal heterogeneity). [41]


 > Results Top


Plasma LPA and CA-125 levels

As shown in [Table 1] and [Figure 1], both plasma LPA and CA-125 levels were higher in ovarian cancer group than benign ovarian tumor group (LPA: Ovarian cancer group: (5.28 ± 1.52) μmol/L; benign ovarian tumor group: (1.82 ± 0.77) μmol/L; CA-125: ovarian cancer group: (87.17 ± 45.81) U/mL; and benign ovarian tumor group: (14.03 ± 10.14) U/mL), which showed statistically significant differences (both P < 0.05).
Figure 1: Comparison of plasma lysophosphatidic acid (LPA) and cancer antigen (CA)-125 levels in ovarian cancer group (OC) and benign ovarian tumor (BOT) group

Click here to view
Table 1: The comparison of the plasma lysophosphatidic acid and cancer antigen 125 levels in ovarian cancer group and benign ovarian neoplasm

Click here to view


Diagnostic value of plasma LPA and CA-125

In [Table 2], pathological results were used as golden standard and the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate of diagnosis of plasma LPA in diagnosing ovarian cancer were 93.33, 89.42, 91.06, 89.42, and 91.52%, respectively; while serum CA-125 were 84.91, 72.65, 73.77, 72.65, and 78.48%, respectively. Thus, LPA with advanced sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate of diagnosis excelled CA-125 in the diagnosis of ovarian cancer (both P < 0.05).
Table 2: The comparison of the plasma lysophosphatidic acid and CA125 levels about sensitivity, specificity, positive predictive value, negative predictive value and accuracy rate of diagnosis

Click here to view


Accuracy rate of diagnosis of LPA and CA-125

As shown in [Table 3], the areas under the receiver operating characteristic (ROC) curve in the diagnosis of ovarian cancer (LPA: 0.983; 95% CI: 0.970-0.995; CA-125: 0.910; 95% CI: 0.872-0.948) were statistically significant compared with the reference (both P < 0.001); and the difference of the areas under the ROC curve between LPA and CA-125 in the diagnosis of ovarian cancer showed statistically significant difference (P < 0.05), indicating that LPA with advanced diagnostic value was better than CA-125 in ovarian cancer. The ROC curves of LPA and CA-125 (nonparametric tests of Hanley-McNeil) in the diagnosis of ovarian cancer are shown in [Figure 2].
Figure 2: Receiver operating characteristic (ROC) curve about plasma LPA and CA-125 in the diagnosis of ovarian cancer

Click here to view
Table 3: The receiver operating characteristic curve about the plasma lysophosphatidic acid and CA125 in the diagnosis of ovarian cancer

Click here to view


Meta-analysis results

A total of 19 case-control studies published between 1996 and 2013 met our selection criteria and enrolled into our final meta-analysis. [17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35] Sixteen studies were performed on Asians (China (n = 15) and[TAG:2][/TAG:2]

Turkey (n = 1)), and the rest three studies on Caucasians (Slovenia (n = 1) and USA (n = 2)). These 19 studies included a total of 2,520 subjects (980 ovarian cancer cases, 872 benign ovarian tumor cases, and 668 healthy controls). Plasma LPA levels in patients and controls were determined by enzyme-linked immunosorbent assay (ELISA; n = 13), bioassay (n = 4), phosphorus determination (n = 1), and inorganic phosphorus (n = 1). As shown in [Figure 3], plasma LPA levels were higher in cancer tissues than in benign tissues (SMD = 2.36, 95% CI: 1.61-3.11, P < 0.001) and normal tissues (SMD = 2.32, 95% CI: 1.77-2.87, P < 0.001).
Figure 3: Comparison of pooled standardized mean differences (SMDs) for LPA levels in cancer tissues, benign tissues, and normal tissues. (a) Cancer tissue vs benign tissue and (b) cancer tissue vs normal tissue

Click here to view



 > Discussion Top


Ovarian cancer has the poorest prognosis among all gynecologic malignancies due to lack of an inability to diagnose ovarian cancer at an early and curable stage, and there has been no significant increase in cure rates during the past 30 years. [42] In the present study, we conducted a case-control report with a meta-analysis using CA-125 as the reference to confirm the correlation between LPA and ovarian cancer. This study demonstrated that LPA showed great value in the diagnosis of ovarian cancer and may be served as a biological index to diagnose ovarian cancer. Ovarian cancer cells can generate LPA by mesothelial cells, forming an autocrine loop mediating growth, survival as well as motility of tumor cells and increasing invasion and metastasis. [43],[44] In our study, both case-control study and meta-analysis including 19 reports provided evidence that the LPA levels were notably higher in ovarian cancer tissues when compared to benign ovarian tumor tissues and normal tissues. Shen et al., also found that plasma LPA levels were quite low in healthy individuals and did not apparently increase in leukemia or breast cancer, while ovarian cancer patients has significantly elevated plasma LPA levels. [45]

Furthermore, the differential diagnosis of ovarian cancer depended on the degree of tumor cell invasion and metastasis by the surrounding microenvironment where invasiveness and infiltration was mediated by the coordinated interaction among growth factors, chemokines, proteases, and various cytokines generated from either tumor cells or normal cells. [46] LPA, at pathological concentrations, can mediate tumor neovascularization, invasion along with metastases, and worsen the prognosis in ovarian malignancies. [47] Through the activation of VEGF's role and its receptor expression of VEGFR-2, LPA plays a part in VEGF and VEGFR-2 complex and modulates the LPA-induced signaling axis, resulting in cell proliferation, migration, and the development of angiogenesis in ovarian cancer, which mediates tumor progression with advanced stage and poor prognosis of ovarian cancer patients. [48] Besides, LPA receptors is provoked to make their effects via the induction of LPA expression, and by LPA2 and LPA3, LPA can upregulate the expression of several angiogenic factors, such as interleukin-6 (IL-6) and IL-8, thus promoting the growth and metastasis of tumor. [42] At the same time, the aberrant production of LPA receptors were considered to excessively act in ovarian cancer patients by stimulating and regulating MMPs secretion, influencing ovarian cancer tumor growth and migration mechanism. [49] In our study, the sensitivity and specificity of plasma LPA used for the diagnosis of ovarian cancer is 93.33 and 84.91%, respectively, both of which were greater compared with serum CA-125. Consistent with our results, Bese et al., reported that LPA with higher sensitivity and specificity can be a more valuable biomarker to detect ovarian cancer pathophysiologic features compared to CA-125. [32]

In summary, our study demonstrated that LPA with advanced sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate of diagnosis shows greater value in the diagnosis of ovarian cancer compared to CA-125 and may be employed as a biological index to diagnose ovarian cancer, and the regulation of plasma LPA levels may be a promising target for genetic therapy of ovarian cancer.


 > Acknowledgments Top


We would like to appreciate the reviewers for their helpful comments on this paper.

 
 > References Top

1.
Chen J, Wang L, Matyunina LV, Hill CG, McDonald JF. Overexpression of miR-429 induces mesenchymal-to-epithelial transition (MET) in metastatic ovarian cancer cells. Gynecol Oncol 2011;121:200-5.  Back to cited text no. 1
    
2.
Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609-15.  Back to cited text no. 2
    
3.
Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212-36.  Back to cited text no. 3
    
4.
Lin HW, Tu YY, Lin SY, Su WJ, Lin WL, Lin WZ, et al. Risk of ovarian cancer in women with pelvic inflammatory disease: A population-based study. Lancet Oncol 2011;12:900-4.  Back to cited text no. 4
    
5.
Rooth C. Ovarian cancer: Risk factors, treatment and management. Br J Nurs 2013;22:S23-30.  Back to cited text no. 5
    
6.
Heidemann LN, Hartwell D, Heidemann CH, Jochumsen KM. The relation between endometriosis and ovarian cancer-a review. Acta Obstet Gynecol Scand 2014;93:20-31.  Back to cited text no. 6
    
7.
Yurkovetsky Z, Skates S, Lomakin A, Nolen B, Pulsipher T, Modugno F, et al. Development of a multimarker assay for early detection of ovarian cancer. J Clin Oncol 2010;28:2159-66.  Back to cited text no. 7
    
8.
Erickson BK, Conner MG, Landen CN Jr. The role of the fallopian tube in the origin of ovarian cancer. Am J Obstet Gynecol 2013;209:409-14.  Back to cited text no. 8
    
9.
Nossov V, Amneus M, Su F, Lang J, Janco JM, Reddy ST, et al. The early detection of ovarian cancer: From traditional methods to proteomics. Can we really do better than serum CA-125? Am J Obstet Gynecol 2008;199:215-23.  Back to cited text no. 9
    
10.
Aoki J, Inoue A, Okudaira S. Two pathways for lysophosphatidic acid production. Biochim Biophys Acta 2008;1781:513-8.  Back to cited text no. 10
    
11.
Lin ME, Herr DR, Chun J. Lysophosphatidic acid (LPA) receptors: Signaling properties and disease relevance. Prostaglandins Other Lipid Mediat 2010;91:130-8.  Back to cited text no. 11
    
12.
Yukiura H, Hama K, Nakanaga K, Tanaka M, Asaoka Y, Okudaira S, et al. Autotaxin regulates vascular development via multiple lysophosphatidic acid (LPA) receptors in zebrafish. J Biol Chem 2011;286:43972-83.  Back to cited text no. 12
    
13.
Inoue S, Tanabe E, Shibata A, Hirane M, Araki M, Dong Y, et al. Ethionine regulates cell motile activity through LPA receptor-3 in liver epithelial WB-F344 cells. Mol Cell Biochem 2013;383:173-7.  Back to cited text no. 13
    
14.
Houben AJ, Moolenaar WH. Autotaxin and LPA receptor signaling in cancer. Cancer Metastasis Rev 2011;30:557-65.  Back to cited text no. 14
    
15.
Hayashi M, Okabe K, Kato K, Okumura M, Fukui R, Fukushima N, et al. Differential function of lysophosphatidic acid receptors in cell proliferation and migration of neuroblastoma cells. Cancer Lett 2012;316:91-6.  Back to cited text no. 15
    
16.
Snider AJ, Zhang Z, Xie Y, Meier KE. Epidermal growth factor increases lysophosphatidic acid production in human ovarian cancer cells: Roles for phospholipase D2 and receptor transactivation. Am J Physiol Cell Physiol 2010;298:C163-70.  Back to cited text no. 16
    
17.
Cao XY. The applicable value of combined detection of LPA, CA1 25 and AFP in the early diagnosis of ovarian cancer. Lab Med Clin 2008;5:1430-1.  Back to cited text no. 17
    
18.
Chen YN, Tao M, Tu FP, Zuo Y, Lu WD. LPA, IL-6 and IL-8 Levels in the Plasma of Patients with Epithelial Ovarian Carcinoma. Pract J Cancer 2008;23:580-2.  Back to cited text no. 18
    
19.
Ding F, Niu B. Clinical significance of detecting lysophosphatidic acid and vascular endothelial growth factor in patients with epithelial ovarian carcinoma. Pract J Med Pharm 2013;30:775-7.  Back to cited text no. 19
    
20.
Du Y. Study on correlation between diagnosis of epithlial ovarian cancer and plasma lysophosphatidic acid. Zhejiang Med J 2005;27:827-8.  Back to cited text no. 20
    
21.
Duan ML, Wu F. The diagnostic value of secretory phospholipase A2 and lysophosphatic acid for ovarian cancer. Chin J Lab Med 2005;28:622-4.  Back to cited text no. 21
    
22.
Guo HY, Han JS, Wu QZ, Yang CS. A study of diagnostic value of plasma lysophosphatidic acid for ovarian epithelial cancer. Chin J Clin Obstet Gynecol 2002;03:36-8.  Back to cited text no. 22
    
23.
Lao M, Pan ZM, Huang WC, Huang LS, Zhu B, Zhao HL, et al. The value of plasma lysophosphatidic acid measurement in the diagnosis of gynecology tumor. Pract J Cancer 2007;22:347-9.  Back to cited text no. 23
    
24.
Li C, Fang SH, Chen W. The diagnostic value of sol uble P185 in ovarian cancer. Chin J Lab Diagn 2007;11:1238-9.  Back to cited text no. 24
    
25.
Lian XF, Li XL, Zhan HL, Sun F. The diagnostic value when lysophospholipids acid, epididymis protein 4 used in early ovarian cancer′ s detection. Int Med Health Guid News 2010;16:2778-81.  Back to cited text no. 25
    
26.
Liang HF, Zhang H, Ma XY. Comparative analysis of the value of lysophosphatidic acid and CA125 in the diagnosis of ovarian cancer. Clin Med China 2011;27:348-50.  Back to cited text no. 26
    
27.
Liao JR, Zong JH, Lv YY. Detection of plasma iysophosphatidic acid (l pa) in epithelial ovarian tumor patients. Inner Mong Med J 2010;42:1295-6.  Back to cited text no. 27
    
28.
Wang DL, Chen LX, Liao XL, Liao XJ, Wu QH. The relationship of lysophosphatidic acid and MMP-2 in diagnosing epithelial ovarian carcinoma. Proc Clin Med 2013;22:403-5.  Back to cited text no. 28
    
29.
Wang H, Chen DZ. Study on the diagnostic value of plasm a lysopho sphatidic Acid (L PA) level determination in patients with ovarian carcinoma. J Radioimmunol 2008;21:355-7.  Back to cited text no. 29
    
30.
Yan ZT, Huang N, Zhao ML, Pang AP. Clinical Values of serum CA125 and LPA determination in early diagnosis of ovarian cancer. Chin J Prim Med Pharm 2009;16:1993-4.  Back to cited text no. 30
    
31.
Zhang YM, Zhang XN. Expression of XIAP, Survivin, LPA and CA12 5 in human epithelial ovarian carcinoma. J Shandong Univ (Health Sci) 2007;45:317-21.  Back to cited text no. 31
    
32.
Bese T, Barbaros M, Baykara E, Guralp O, Cengiz S, Demirkiran F, et al. Comparison of total plasma lysophosphatidic acid and serum CA-125 as a tumor marker in the diagnosis and follow-up of patients with epithelial ovarian cancer. J Gynecol Oncol 2010;21:248-54.  Back to cited text no. 32
    
33.
Murph M, Tanaka T, Pang J, Felix E, Liu S, Trost R, et al. Liquid chromatography mass spectrometry for quantifying plasma lysophospholipids: Potential biomarkers for cancer diagnosis. Methods Enzymol 2007;433:1-25.  Back to cited text no. 33
    
34.
Pozlep B, Meleh M, Kobal B, Verdenik I, Osredkar J, Kralj LZ, et al. Use of lysophosphatidic acid in the management of benign and malignant ovarian tumors. Eur J Gynaecol Oncol 2007;28:394-9.  Back to cited text no. 34
    
35.
Xu Y, Shen Z, Wiper DW, Wu M, Morton RE, Elson P, et al. Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers. JAMA 1998;280:719-23.  Back to cited text no. 35
    
36.
Holt GR. Declaration of Helsinki-the world′s document of conscience and responsibility. South Med J 2014;107:407.  Back to cited text no. 36
    
37.
Pereira A, Perez-Medina T, Magrina JF, Magtibay PM, Rodriguez-Tapia A, Peregrin I, et al. International Federation of gynecology and obstetrics staging classification for cancer of the ovary, fallopian tube, and peritoneum: Estimation of survival in patients with node-positive epithelial ovarian cancer. Int J Gynecol Cancer 2015;25:49-54.  Back to cited text no. 37
    
38.
Chao A, Tang YH, Lai CH, Chang CJ, Chang SC, Wu TI, et al. Potential of an age-stratified CA125 cut-off value to improve the prognostic classification of patients with endometrial cancer. Gynecol Oncol 2013;129:500-4.  Back to cited text no. 38
    
39.
Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol 2005;28:123-37.  Back to cited text no. 39
    
40.
Jackson D, White IR, Riley RD. Quantifying the impact of between-study heterogeneity in multivariate meta-analyses. Stat Med 2012;31:3805-20.  Back to cited text no. 40
    
41.
Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to detect publication bias in meta-analysis. JAMA 2006;295:676-80.  Back to cited text no. 41
    
42.
Sedlakova I, Vavrova J, Tosner J, Hanousek L. Lysophosphatidic acid (LPA)-a perspective marker in ovarian cancer. Tumour Biol 2011;32:311-6.  Back to cited text no. 42
    
43.
Seo JH, Jeong KJ, Oh WJ, Sul HJ, Sohn JS, Kim YK, et al. Lysophosphatidic acid induces STAT3 phosphorylation and ovarian cancer cell motility: Their inhibition by curcumin. Cancer Lett 2010;288:50-6.  Back to cited text no. 43
    
44.
Ren J, Xiao YJ, Singh LS, Zhao X, Zhao Z, Feng L, et al. Lysophosphatidic acid is constitutively produced by human peritoneal mesothelial cells and enhances adhesion, migration, and invasion of ovarian cancer cells. Cancer Res 2006;66:3006-14.  Back to cited text no. 44
    
45.
Shen Z, Wu M, Elson P, Kennedy AW, Belinson J, Casey G, et al. Fatty acid composition of lysophosphatidic acid and lysophosphatidylinositol in plasma from patients with ovarian cancer and other gynecological diseases. Gynecol Oncol 2001;83:25-30.  Back to cited text no. 45
    
46.
Yan Y, Liang H, Li R, Xie L, Li M, Li S, et al. XRCC3 Thr241Met polymorphism and ovarian cancer risk: A meta-analysis. Tumour Biol 2014;35:2711-5.  Back to cited text no. 46
    
47.
Dutta S, Wang FQ, Wu HS, Mukherjee TJ, Fishman DA. The NF-kappaB pathway mediates lysophosphatidic acid (LPA)-induced VEGF signaling and cell invasion in epithelial ovarian cancer (EOC). Gynecol Oncol 2011;123:129-37.  Back to cited text no. 47
    
48.
Yu S, Murph MM, Lu Y, Liu S, Hall HS, Liu J, et al. Lysophosphatidic acid receptors determine tumorigenicity and aggressiveness of ovarian cancer cells. J Natl Cancer Inst 2008;100:1630-42.  Back to cited text no. 48
    
49.
Wang FQ, Ariztia EV, Boyd LR, Horton FR, Smicun Y, Hetherington JA, et al. Lysophosphatidic acid (LPA) effects on endometrial carcinoma in vitro proliferation, invasion, and matrix metalloproteinase activity. Gynecol Oncol 2010;117:88-95.  Back to cited text no. 49
    


    Figures

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

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Materials and me...>Results>Discussion>Acknowledgments>Article Figures>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed2158    
    Printed44    
    Emailed1    
    PDF Downloaded106    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]