| Background and objectiveOvarian cancer(OC)is the highest fatality rate of gynecologic malignancies.The high mortality rate of ovarian cancer is related to the difficulties of early diagnosis.Early ovarian cancer generally absents obvious symptoms,and there is no effective means of early diagnosis.Therefore,many patients are in advanced stage at diagnosis.Looking for valuable blood or tissue diagnosis biomarkers of ovarian cancer has been a hot clinical research,but has no major breakthrough so far.Folate-receptor 1(FOLR1)protein is a glycosylphosphatidylinositol(GPI)-conjugated glycoprotein and encoded by the FOLR1 gene with a molecular mass of38-40 kD.FOLR1 has a high affinity for folic acid and its derivatives.Studies have shown that FOLR1 is overexpressed in specific epithelial-derived malignancies,but FOLR1 expression is low in normal tissues.And FOLR1 can be shed from the cell surface into the bloodstream.Serum FOLR1 levels may have clinical value in the diagnosis of ovarian cancer,disease judgment,treatment effect monitoring and prognosis evaluation,but the corresponding research is lacking.This study was aimed to investigate the relationship between the level of FOLR1and clinicopathological parameters in patients with epithelial ovarian cancer(EOC),and to compare the diagnostic value of FOLR1 and CA125 in epithelial ovarian cancer.We also analyzed the correlation between serum FOLR1 level and FOLR1expression in ovarian cancer tissues.Materials and methods1.Study objectPatients were recruited in the Third Affiliated Hospital of Zhengzhou University from October 2014 to May 2017.The malignant group consisted of 44 patients with epithelial ovarian cancer.All patients had no other tumor history and did not receive radiotherapy and chemotherapy before surgery.38 patients with benign epithelial ovarian tumors were selected as benign group.All patients received surgical treatment.All patients were collected from 3 mL of fasting venous blood in the morning before surgery,and the ovarian tumor tissues were removed during operation.The tissue specimens were pathologically verified after surgery.22 healthy women who had physical examination in our hospital during the same period were selected as the normal group.All individuals were collected morning fasting venous blood 3mL.22 patients who had undergone oophorectomy due to benign gynecological diseases were selected as the normal group.The specimens of normal ovarian tissues that were removed during surgery were collected and confirmed by pathologist after operation.All patients were informed concent to participate in this research and the study was approved by the Ethics Committee.2.Experimental methods(1)Preoperative serum FOLR1 level was detected by ELISA,and preoperative serum CA125 level was detected by microparticle chemiluminescence.(2)qRT-PCR was used to detect the expression of FOLR1 mRNA in tissues of each group.(3)The expression of FOLR1 protein in tissues of each group was detected by immunohistochemical SP method.3.Statistical analysisSPSS 21.0 was used for statistical analysis.The normal distribution measurement data is represented by?x±s and the abnormal distribution quantitative data is represented by M(P25 to P75).Two sets of quantitative data were analyzed by independent sample t-test,and multiple sets of quantitative data were analyzed by one-way ANOVA or rank-sum test.The ROC(Receiver operating characteristic,receiver operating characteristic)curve was plotted to compare the levels of serum FOLR1 and CA125 in the diagnosis of epithelial ovarian cancer.The cut-off value was calculated using the maximum Yooden~’s index.Count data were expressed as a percentage and statistical analysis was performed using the?~2 test and Fisher’s exact probability method.The correlation analysis uses the Spearman rank correlation method.The test level isα=0.05(The level of comparison between the two groups wasα’=α/3=0.0167).Results1.The levels of serum FOLR1 and CA125The levels of serum FOLR1 in the malignant,benign,and normal groups were535.88±315.34,124.57±63.53,124.03±50.65 pg/mL,,respectively.the levels of serum CA125 were 87.40(26.87 to 280.18)and 26.64(12.99~72.50)、26.64(14.28~34.10)pg/mL in the malignant,benign,and normal groups,respectively.The levels of serum FOLR1 and CA125 in the malignant group were higher than those in the benign group and the normal group,and the differences were statistically significant(P<0.01).The levels of serum FOLR1 in the benign group was similar to normal group,with no statistically significant difference(P>0.05).The levels of serum CA125 in the benign group was similar to the normal group,with no significant difference(P>0.05).2.Relationship between serum FOLR1 and clinicopathological parameters in epithelial ovarian cancer groupFurther analysis of the relationship between serum FOLR1 levels and clinicopathological parameters in malignant patients showed that the serum levels of FOLR1 in FIGOⅠ~ⅡandⅢ~Ⅳgroups were 273.39±152.29 and 853.90±631.70 pg/mL,respectively.The levels of serum FOLR1 increased with the progression of pathology,and the difference was statistically significant(P<0.05).The levels of FOLR1 were 211.26±129.10,403.12±214.67 and 1190.56±630.00pg/mL in high,moderate and poorly differentiated groups,respectively.The levels of serum FOLR1 gradually increased with the decrease of tissue differentiation(P<0.01).The serum levels of FOLR1 were 696.78±488.00 and 211.20±115.04 pg/mL in groups with cystadenocarcinoma and non-serous cystadenocarcinoma,respectively.Serous cystadenocarcinoma had higher levels of serum FOLR1 and the difference was statistically significant(P<0.05).The levels of serum FOLR1 in groups with and without lymph node metastasis were 897.16±511.33 and 276.37±136.90pg/mL,respectively.Serum levels of FOLR1 were significantly higher in patients with lymph node metastasis and the difference was statistically significant(P<0.05).The levels of serum FOLR1 in positive and negative ascitic fluid cytology groups were896.54±561.25,206.80±120.03 pg/mL,respectively.The serum levels of FOLR1were higher in the ascites cytology test positive patients,and the difference was statistically significant(P<0.05).3.Diagnostic efficacy of serum FOLR1 and CA125 in epithelial ovarian cancerROC curves were plotted.The area under curve(AUC)of FOLR1 in diagnosis of epithelial ovarian cancer was 0.81(95%CI:0.72~0.88),the Youden’s index was0.51 and the cut-off value was 215pg/mL.With the cut-off value,the sensitivity and specificity of the diagnosis of epithelial ovarian cancer were 61.4%and 98.0%,respectively,and the positive rate of serum FOLR1 in early epithelial ovarian cancer was 67%(12/18).The AUC of serum CA125 for diagnosing epithelial ovarian cancer was 0.72(95%CI:0.63~0.81),the Youden’s index was 0.39,the cut-off value of 73U/mL.the sensitivity was 59.1%and the specificity was 80.0%.In terms of AUC,the difference between serum FOLR1 and CA125 was not statistically significant(P>0.05).4.Expression of FOLR1 mRNA in TissuesThe relative expression levels of FOLR1 mRNA in malignant,benign,and normal tissues were 3.425±2.341,1.302±0.454,and 1.155±0.501,respectively.The malignant group was higher than the benign group and the normal group,the difference was statistically significant(P<0.01);the benign group was higher than the normal group,and the difference was not statistically significant(P>0.05).Furthermore,Spearman’s rank correlation analysis was performed on the relationship between serum FOLR1 levels and tumor tissues FOLR1 mRNA relative expression in malignant patients.The results showed a positive correlation between the two(r=0.635,P<0.001).5.Expression of FOLR1 protein in tissuesThe expression of FOLR1 protein was positive in different degrees in malignant tissues and the positive expression rate was 86.4%(38/44).Spearman rank correlation analysis showed that there was a positive correlation between serum FOLR1 level and tumor tissues FOLR1 protein expression(r=0.876,P<0.001).FOLR1 was negative in benign and normal tissues.Conclusion1.The level of serum FOLR1 was increased in malignant group,which was positively correlated with the expression of FOLR1 in tissues of ovarian cancer group.2.In the diagnosis of epithelial ovarian cancer,serum FOLR1 can achieve similar diagnostic efficacy as CA125.3.Detection of serum FOLR1 levels contribute to the diagnosis and disease judgment of epithelial ovarian cancer. |
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