[1]刘 端,李红雨,臧星卉,等.VEGF、MMP-9在卵巢癌组织中的表达及贝伐单抗联合顺铂对卵巢癌细胞SKOV3的作用[J].郑州大学学报(医学版),2018,(04):516-520.[doi:10.13705/j.issn.1671-6825.2017.11.088]
 LIU Duan,LI Hongyu,ZANG Xinghui,et al.Expressions of VEGF and MMP-9 in ovarian cancer tissue and effects of bevacizumab plus cisplatin on ovarian cancer SKOV3 cells[J].JOURNAL OF ZHENGZHOU UNIVERSITY(MEDICAL SCIENCES),2018,(04):516-520.[doi:10.13705/j.issn.1671-6825.2017.11.088]
点击复制

VEGF、MMP-9在卵巢癌组织中的表达及贝伐单抗联合顺铂对卵巢癌细胞SKOV3的作用()
分享到:

《郑州大学学报(医学版)》[ISSN:1671-6825/CN:41-1340/R]

卷:
期数:
2018年04期
页码:
516-520
栏目:
应用研究
出版日期:
2018-07-20

文章信息/Info

Title:
Expressions of VEGF and MMP-9 in ovarian cancer tissue and effects of bevacizumab plus cisplatin on ovarian cancer SKOV3 cells
作者:
刘 端李红雨臧星卉鱼志琪孙 玮李玉光
郑州大学第三附属医院妇产科 郑州 450052
Author(s):
LIU Duan LI Hongyu ZANG Xinghui YU Zhiqi SUN Wei LI Yuguang
Department of Gynecology and Obstetrics, the Third Affiliated Hospital, Zhengzhou University, Zhengzhou 450052
关键词:
卵巢癌 血管内皮生长因子 基质金属蛋白酶-9 贝伐单抗 顺铂 SKOV3细胞
Keywords:
ovarian cancer VEGF MMP-9 bevacizumab cisplatin SKOV3 cell
分类号:
R737.3
DOI:
10.13705/j.issn.1671-6825.2017.11.088
摘要:
目的:探讨卵巢癌组织中VEGF、MMP-9蛋白的表达及贝伐单抗联合顺铂对卵巢癌细胞SKOV3的作用机制。方法:收集41例上皮性卵巢恶性肿瘤组织、30例卵巢良性肿瘤组织、30例正常卵巢组织,采用免疫组化法检测卵巢组织中VEGF、MMP-9蛋白的表达情况。MTT实验检测2.5、5.0、10.0、20.0、40.0 mg/L的贝伐单抗对卵巢癌细胞SKOV3的体外增殖抑制作用; 流式细胞仪检测5 mg/L贝伐单抗、3 mg/L顺铂单独及联合使用对卵巢癌细胞凋亡的影响; Western blot法检测5 mg/L贝伐单抗、3 mg/L顺铂单独及联合使用对VEGF下游信号通路中关键蛋白AKT、Bad和MMP-9表达的影响。结果:卵巢癌、卵巢良性肿瘤、正常卵巢组织中VEGF蛋白阳性表达率分别为75.6%、40.0%、6.7%; MMP-9蛋白阳性表达率分别为70.7%、20.0%、3.3%,卵巢癌组与卵巢良性肿瘤组和对照组相比均升高(P均<0.001)。贝伐单抗在体外可浓度依赖性地抑制卵巢癌细胞SKOV3的增殖,其IC50为(8.89±0.27)mg/L。贝伐单抗、顺铂可联合诱导卵巢癌细胞SKOV3凋亡(P<0.001); 贝伐单抗联合顺铂处理组与单独药物处理组相比,可减弱磷酸化AKT和MMP-9蛋白的表达,增强促凋亡蛋白Bad的表达。结论:VEGF、MMP-9在卵巢癌组织中呈共同高表达状态; 贝伐单抗联合顺铂通过对VEGF下游信号通路的调控以及MMP-9蛋白的影响,发挥协同抗肿瘤效应。
Abstract:
Aim: To detect expressions of VEGF and MMP-9 in ovarian cancer tissue and explore mechanism of bevacizumab plus cisplatin on ovarian cancer SKOV3 cells.Methods: A total of 41 epithelial ovarian malignant tumors, 30 cases of benign ovarian tumor, 30 cases of normal ovarian tissue from ovariectomy were collected. Immunohistochemistry was used to detect the expressions of VEGF and MMP-9 in ovarian tissue. The effect of bevacizumab(2.5, 5.0, 10.0, 20.0, 40.0 mg/L)on SKOV3 cells was detected by MTT assay. Flow cytometry was used to detect the apoptosis of ovarian cancer cells which were treated with bevacizumab(5 mg/L)or cisplatin(3 mg/L)alone or in combination,and Western blot was used to detect the expressions of AKT,Bad, and MMP-9,the key downstream proteins of VEGF signal pathway.Results: The positive expression rates of VEGF in ovarian cancer, benign ovarian tumor and normal ovarian tissue were 75.6%, 40.0% and 6.7%, respectively(P<0.001),and the positive rates of MMP-9 were 70.7%, 20.0% and 3.3%, respectively(P<0.001). Bevacizumab inhibited the proliferation of ovarian cancer cells in a concentration-dependent manner, and the IC50 value of bevacizumab was(8.89±0.27)mg/L. The interaction between bevacizumab and cisplatin was significant(P<0.001), the combined use of bevacizumab and cisplatin performed best compared to the use alone, and synergistic induction of apoptosis in ovarian cancer cells. The bevacizumab plus cisplatin significantly reduced the expression of phosphorylated AKT and MMP-9 protein, and enhanced the expression of the pro-apoptotic protein Bad when compared with bevacizumab or cisplatin alone.Conclusion: VEGF and MMP-9 are overexpressed in ovarian cancer tissue. Bevacizumab combined with cisplatin exerts a synergistic antitumor effect through the regulation of VEGF signaling pathway and MMP-9 protein.

参考文献/References:

[1] SIEGEL RL,MILLER KD,JEMAL A.Cancer statistics[J].JAMA,2013,310(9):982
[2] LOIZZI V,DEL VECCHIO V,GARGANO G,et al.Biological pathways involved in tumor angiogenesis and bevacizumab based anti-angiogenic therapy with special references to ovarian cancer[J].Int J Mol Sci,2017,18(9):E1967
[3] ALASSEM A,ALHAZZANI K,DONDAPATI P,et al.Matrix metalloproteinases:a challenging paradigm of cancer management[J].Semin Cancer Biol,2017.doi:10.1016/j.semcancer.2017.11.008
[4] BOWER NI,VOGRIN AJ,LE GUEN L,et al.Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development[J].Development,2017,144(3):507
[5] CARMELIET P.Angiogenesis in life, disease and medicine[J].Nature,2005,438(770):932
[6] POTENTE M,GERHARDT H,CARMELIET P.Basic and therapeutic aspects of angiogenesis[J].Cell,2011,146(6):873
[7] ZHAO Q,LI Z.Angiogenesis[J]. Biomed Res Int,2015,2015:135861
[8] DERYUGINA EI,QUIGLEY JP.Matrix metalloproteinases and tumor metastasis[J].Cancer Metastasis Rev,2006,25(1):9
[9] BERGERS G,BREKKEN R,MCMAHON G,et al.Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis[J].Nat Cell Biol,2000,2(10):737
[10]魏萍,盛修贵.整合素αvβ6、MMP-9在46例卵巢上皮癌表达及意义[J].肿瘤学杂志,2010,16(4):305
[11]GUPTA MK,QIN RY.Mechanism and its regulation of tumor-induced angiogenesis[J].World J Gastroenterol,2003,9(6):1144
[12]HUANG S,HE P,PENG X,et al.Pristimerin inhibits prostate cancer bone metastasis by targeting PC-3 stem cell characteristics and VEGF-induced vasculogenesis of BM-EPCs[J].Cell Physiol Biochem,2015,37(1):253
[13]OKAMOTO S,NITTA M,MARUYAMA T,et al.Bevacizumab changes vascular structure and modulates the expression of angiogenic factors in recurrent malignant gliomas[J].Brain Tumor Pathol,2016,33(2):129
[14]FLEMING ND,COLEMAN RL,TUNG CA,et al.Phase Ⅱ trial of bevacizumab with dose-dense paclitaxel as first-line treatment in patients with advanced ovarian cancer[J].Gynecol Oncol,2017,147(1):41
[15]GOEY KK,ELIAS SG,HINKE A,et al.Clinicopathological factors influencing outcome in metastatic colorectal cancer patients treated with fluoropyrimidine and bevacizumab maintenance treatment vs observation: an individual patient data meta-analysis of two phase 3 trials[J].Br J Cancer,2017,117(12):1768
[16]TAKAYOSHI K,KUSABA H,UENOMACHI M,et al.Suggestion of added value by bevacizumab to chemotherapy in patients with unresectable or recurrent small bowel cancer[J].Cancer Chemother Pharmacol,2017,80(2):333
[17]MENG X,ZHAO R,SHEN G,et al.Efficacy and safety of bevacizumab treatment for refractory brain edema: case report[J].Medicine(Baltimore),2017,96(44):e8280
[18]AL-ALEM L,CURRY J.Ovarian cancer: involvement of the matrix metalloproteinases[J].Reproduction,2015,150(2):R55

相似文献/References:

[1]李留霞),王甜甜),王凯娟),等.六种肿瘤相关抗原自身抗体微阵列诊断卵巢癌的价值[J].郑州大学学报(医学版),2009,(06):1235.
 LI Liuxia),WANG Tiantian),WANG Kaijuan),et al.Value of detecting autoantibodies to six tumorassociated antigens miniarray for ovarian cancer diagnosis[J].JOURNAL OF ZHENGZHOU UNIVERSITY(MEDICAL SCIENCES),2009,(04):1235.
[2]朱宝菊),乔玉环)#,李印).canstatin基因治疗对小鼠人卵巢癌移植瘤生长及Caspase3、Flk1蛋白表达的影响*[J].郑州大学学报(医学版),2009,(02):292.
 ZHU Baoju),QIAO Yuhuan),LI Yin).Effects of canstatin gene theraphy on expression of Flk1 and Caspase3 and growth of human ovarian cancer in mice[J].JOURNAL OF ZHENGZHOU UNIVERSITY(MEDICAL SCIENCES),2009,(04):292.
[3]刘慧冰),史惠蓉)#,张瑞涛),等.卵巢癌组织中CDK1和CDC25B的表达*[J].郑州大学学报(医学版),2009,(02):312.
 LIU Huibing),SHI Huirong),ZHANG Ruitao),et al.Expression of CDK1 and CDC25B in epithelial ovarian cancer tissue[J].JOURNAL OF ZHENGZHOU UNIVERSITY(MEDICAL SCIENCES),2009,(04):312.
[4]樊冬梅,史惠蓉#,陈志敏,等.卵巢癌组织中胃泌素释放肽及其受体的表达*[J].郑州大学学报(医学版),2011,(04):550.
 FAN Dongmei,SHI Huirong,CHEN Zhimin,et al.Expression of gastrinreleasing peptide and its receptor in ovarian cancer tissue[J].JOURNAL OF ZHENGZHOU UNIVERSITY(MEDICAL SCIENCES),2011,(04):550.
[5]郭玉琪,田捧,路平,等.Siltuximab单克隆抗体对荷耐紫杉醇卵巢癌细胞株裸鼠肿瘤生长的影响*[J].郑州大学学报(医学版),2011,(05):703.
 GUO Yuqi,TIAN Peng,LU Ping,et al.Effects of Siltuximab on tumor growth in nude mice loded by paclitaxel resistant ovarian cancer cells[J].JOURNAL OF ZHENGZHOU UNIVERSITY(MEDICAL SCIENCES),2011,(04):703.
[6]王军△,尚凤伟,朱登纳,等.银杏内酯B对缺氧缺血性脑损伤新生大鼠脑组织Caspase3及VEGF mRNA表达的影响*[J].郑州大学学报(医学版),2013,(02):175.
 WANG Jun,SHANG Fengwei,ZHU Dengna,et al.Effects of ginkgolide B on expression of Caspase3 and VEGF mRNA in brain tissue of newborn rats with hypoxicischemic brain damage[J].JOURNAL OF ZHENGZHOU UNIVERSITY(MEDICAL SCIENCES),2013,(04):175.
[7]李留霞)#,张兰兰),李秀芳),等.六种肿瘤相关抗原自身抗体联合CA125检测对卵巢癌早期诊断的价值*[J].郑州大学学报(医学版),2013,(02):238.
 LI Liuxia),ZHANG Lanlan),LI Xiufang),et al.Evaluation of detecting autoantibodies against six tumorassociated antigens with CA125 in early diagnosis of ovarian cancer[J].JOURNAL OF ZHENGZHOU UNIVERSITY(MEDICAL SCIENCES),2013,(04):238.
[8]杨香丽,黄冬梅#,孙欣欣.卵巢癌术后2种治疗方案疗效分析[J].郑州大学学报(医学版),2014,(04):587.
[9]张根豪),刘俊文),苏利沙),等.阿司匹林对人卵巢癌组织和SKOV3细胞SOX7表达和Wnt/βcatenin信号通路的影响*[J].郑州大学学报(医学版),2015,(02):240.
 ZHANG Genhao),LIU Junwen),SU Lisha,et al.Effect of aspirin on expression of SOX7 and Wnt/βcatenin signaling pathway in human ovarian cancer tissue and SKOV3 cells[J].JOURNAL OF ZHENGZHOU UNIVERSITY(MEDICAL SCIENCES),2015,(04):240.
[10]刘海燕,娄季宇#,白宏英,等.脑梗死大鼠缺血脑组织中Slit2蛋白的表达及与血管新生的关系[J].郑州大学学报(医学版),2015,(05):655.
 LIU Haiyan,LOU Jiyu,BAI Hongying,et al.Expression of Slit2 protein in infarction brain tissue and its correlation with angiogenesis in rats with cerebral infarction[J].JOURNAL OF ZHENGZHOU UNIVERSITY(MEDICAL SCIENCES),2015,(04):655.

备注/Memo

备注/Memo:
【作者简介】李红雨,通信作者,女,1964年9月生,博士,教授,主任医师,研究方向:妇科肿瘤,E-mail:lihongyu99@qq.com
更新日期/Last Update: 2018-06-20