上皮性卵巢癌患者血清外泌体miR-200c与组织NRP1表达、辅助化疗反应及预后的关系-东南大学学报医学版

上皮性卵巢癌患者血清外泌体miR-200c与组织NRP1表达、辅助化疗反应及预后的关系

单位：咸阳市第一人民医院妇科, 陕西咸阳 712000

分类号：R737.31

出版年·卷·期（页码）：2023·42·第五期（649-657）

摘要：

目的:探讨上皮性卵巢癌(EOC)患者血清外泌体微小RNA(miR)-200c与组织神经纤毛蛋白1(NRP1)表达、化疗反应及预后的关系。方法:纳入2018年2月至2022年10月期间在本院接受初级减瘤手术和辅助化疗的135例EOC患者,另外纳入30例良性肿瘤患者作为对照。术前3 d采集患者血清样本,提取并纯化血清外泌体,通过实时荧光定量PCR法检测血清外泌体miR-200c表达水平。术中收集135例EOC癌组织、48例癌旁正常组织和30例良性肿瘤组织样本,通过免疫组织化学法评估组织NRP1蛋白表达。118例患者术后完成至少6个疗程的标准化疗方案,化疗完成后>6个月无复发视为化疗敏感。化疗耐药定义为原发性化疗难治性患者或化疗完成后 ≤ 6个月复发。结果:EOC组织中NRP1蛋白阳性表达率高于癌旁正常卵巢组织和良性肿瘤组织(P<0.001)。与良性肿瘤患者相比,EOC患者血清外泌体miR-200c表达水平显著降低(P<0.001)。血清外泌体miR-200c水平可良好地区分EOC患者和良性肿瘤患者,ROC曲线下面积(AUC)为0.955(95%CI 0.921~0.989)。EOC患者血清外泌体miR-200c水平与组织NRP1表达呈负相关(P<0.001)。血清外泌体miR-200c表达水平在化疗耐药组患者中更低(P<0.001),其预测EOC患者化疗反应的AUC为0.846(95%CI 0.769~0.924)。Cox回归和Kaplan-Meier预后分析显示,血清外泌体miR-200c低表达是导致EOC患者更短总生存期(OS)和无进展生存期(PFS)的独立危险因素(P<0.05)。结论:血清外泌体miR-200c低表达与组织NRP1高表达、化疗耐药及预后不良有关,有希望作为术前预测EOC化疗反应和预后的生物标志物。

Objective: To investigate the relationship between serum exosomal microRNA(miR)-200c and tissue neuropilin 1(NRP1) expression, chemotherapy response and prognosis in patients with epithelial ovarian cancer(EOC). Methods: A total of 135 patients with EOC who received primary reductive surgery and adjuvant chemotherapy at our hospital between February 2018 and October 2022 were included, and another 30 patients with benign tumors were included as controls.Serum samples were collected 3 days before surgery, serum exosomes were extracted and purified, and the expression level of serum exosomal miR-200c was detected by real-time fluorescence quantitative PCR. 135 EOC cancer tissue, 48 paracancer normal tissue and 30 benign tumor tissue samples were collected during the operation, and NRP1 protein expression was evaluated by immunohistochemistry. 118 patients completed at least 6 courses of standard chemotherapy. Patients were considered sensitive to chemotherapy when no recurrence >6 months after completion of chemotherapy. Chemotherapy resistance was defined as relapse in patients refractory to primary chemotherapy or recurrence ≤ 6 months after completion of chemotherapy. Results: The positive expression rate of NRP1 protein in EOC was higher than that in paracancer normal ovarian tissue and benign tumor tissue(P<0.001). The expression level of serum exosomal miR-200c was significantly lower in patients with EOC than in patients with benign tumors(P<0.001). The level of serum exosomal miR-200c well distinguished EOC from benign tumors, with an area under the curve(AUC) of 0.955(95%CI 0.921-0.989). The level of exosomal miR-200c in patients with EOC was negatively correlated with the expression of NRP1 in tissues(P<0.001). The expression level of serum exosomal miR-200c was lower in the chemotherapy resistant group(P<0.001), and the AUC predicting chemotherapy response in patients with EOC was 0.846(95%CI 0.769-0.924). In Cox regression and Kaplan-Meier prognostic analyses, low expression of serum exosomal miR-200c was an independent risk factor for shorter overall survival(OS) and progression-free survival(PFS) in patients with EOC(P<0.05). Conclusion: Low expression of serum exosomal miR-200c is associated with high expression of tissue NRP1, chemotherapy resistance and poor prognosis, and can be used as a promising biomarker to predict chemotherapy response and prognosis of EOC before surgery.

参考文献：

[1] SIEGEL R L,MILLER K D,WAGLE N S,et al.Cancer statistics,2023[J].CA Cancer J Clin,2023,73(1):17-48.
[2] GAONA-LUVIANO P,MEDINA-GAONA L A,MAGAÑA-PÉREZ K.Epidemiology of ovarian cancer[J].Chin Clin Oncol,2020,9(4):47-52.
[3] 栗宝华,赵丽嫣.激素和上皮性卵巢癌研究新进展[J].中国妇产科临床杂志,2003,4(3):223-226.
[4] 董倩,龙潇冉,狄文.长链非编码RNA及相关微小RNA在卵巢癌中的研究进展[J].国际妇产科学杂志,2020,47(3):327-331,339.
[5] YANG L,XIE H J,LI Y Y,et al.Molecular mechanisms of platinum-based chemotherapy resistance in ovarian cancer(Review)[J].Oncol Rep,2022,47(4):82-91.
[6] 曹美婷,耿海燕,贾海霞,等.新辅助化疗结合手术治疗晚期卵巢癌的近期疗效及远期疗效观察[J].肿瘤药学,2022,12(4):508-513.
[7] ZHANG W,SU X,LI S,et al.Low serum exosomal miR-484 expression predicts unfavorable prognosis in ovarian cancer[J].Cancer Biomark,2020,27(4):485-491.
[8] KIM S,CHOI M C,JEONG J Y,et al.Serum exosomal miRNA-145 and miRNA-200c as promising biomarkers for preoperative diagnosis of ovarian carcinomas[J].J Cancer,2019,10(9):1958-1967.
[9] 叶宁珍,赵绍杰,王高莹,等.外泌体miRNA在妇产科疾病中的研究进展[J].南京医科大学学报(自然科学版),2021,41(6):932-936.
[10] HUANG X,YAN Y,GUI A,et al.A Regulatory loop involving miR-200c and NF-κB modulates mortalin expression and increases cisplatin sensitivity in an ovarian cancer cell line model[J].Int J Mol Sci,2022,23(23):15300-15315.
[11] VESCARELLI E,GERINI G,MEGIORNI F,et al.MiR-200c sensitizes olaparib-resistant ovarian cancer cells by targeting neuropilin 1[J].J Exp Clin Cancer Res,2020,39(1):3-15.
[12] SUNDARARAJAN V,BURK U C,BAJDAK-RUSINEK K.Revisiting the miR-200 family:a clan of five siblings with essential roles in development and disease[J].Biomolecules,2022,12(6):781-806.
[13] FERNÁNDEZ-PALANCA P,PAYO-SERAFÍN T,FONDEVILA F,et al.Neuropilin-1 as a potential biomarker of prognosis and invasive-related parameters in liver and colorectal cancer:a systematic review and meta-analysis of human studies[J].Cancers(Basel),2022,14(14):3455-3477.
[14] 李婧,崔自明,陈雅卓,等.神经纤毛蛋白1在卵巢癌组织标本中的表达及临床意义[J].中国组织化学与细胞化学杂志,2021,30(1):59-64,74.
[15] CHEN C,HU Y,LI L.NRP1 is targeted by miR-130a and miR-130b,and is associated with multidrug resistance in epithelial ovarian cancer based on integrated gene network analysis[J].Mol Med Rep,2016,13(1):188-196.
[16] PRAT J,FIGO Committee on Gynecologic Oncology.Staging classification for cancer of the ovary,fallopian tube,and peritoneum[J].Int J Gynaecol Obstet,2014,124(1):1-5.
[17] ARMSTRONG D K,ALVAREZ R D,BAKKUM-GAMEZ J N,et al.Ovarian Cancer,Version 2.2020,NCCN Clinical Practice Guidelines in Oncology[J].J Natl Compr Canc Netw,2021,19(2):191-226.
[18] CUI J,WANG H,ZHANG X,et al.Exosomal miR-200c suppresses chemoresistance of docetaxel in tongue squamous cell carcinoma by suppressing TUBB3 and PPP2R1B[J].Aging(Albany NY),2020,12(8):6756-6773.
[19] YANG C,LI H,ZHANG T,et al.miR-200c overexpression inhibits the invasion and tumorigenicity of epithelial ovarian cancer cells by suppressing lncRNA HOTAIR in mice[J].J Cell Biochem,2020,121(2):1514-1523.
[20] MENG X,MÜLLER V,MILDE-LANGOSCH K,et al.Diagnostic and prognostic relevance of circulating exosomal miR-373,miR-200a,miR-200b and miR-200c in patients with epithelial ovarian cancer[J].Oncotarget,2016,7(13):16923-16935.

服务与反馈：

【文章下载】【发表评论】【查看评论】【加入收藏】

提示：您还未登录，请登录！点此登录