术前新辅助化疗对宫颈癌患者手术切除病灶内恶性分子表达的影响
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摘要
目的研究术前新辅助化疗对宫颈癌患者手术切除病灶内恶性分子表达的影响。方法选择2015年3月—2017年6月期间在南方医科大学附属小榄医院妇产科诊断为Ⅰb2和Ⅱa2期宫颈癌患者118例,随机数字表法分为2组各59例,试验组接受新辅助化疗联合手术切除,对照组直接接受手术切除治疗。取手术切除的宫颈癌组织,测定促增殖分子[Ki-67、人细胞周期相关激酶(CCRK)、细胞周期蛋白Bl(CyclinB1)、细胞周期蛋白依赖性激酶1(CDK1)、Polo样激酶1 (Plk1)、生成素(Survivin)]、抑癌基因[多亮氨酸重复区免疫球蛋白样蛋白1(LRIG1)、p16基因、真核起始因子4E3(eIF4E3)、N-myc下游调节基因4(NDRG4)、Ras相关结构域因子2A(RASSF-2A)、增强子结合蛋白1(Ebp1)]及侵袭基因[β-连环蛋白(β-catenin)、基质金属蛋白酶-8(MMP-8)、解聚素—金属蛋白酶19(ADAM19)、金属蛋白酶组织抑制剂1 (TIMP1)、E-钙黏蛋白(E-cadherin)]的表达量。结果试验组患者的宫颈癌病灶内促增殖分子Ki-67、CCRK、CyclinB1、CDK1、Plk1、Survivin和促侵袭基因β-catenin、MMP8、ADAM19的mRNA表达量显著低于对照组(t=22.019、26. 009、15.096、21. 991、26. 727、14. 592、14. 309、21. 111、18. 154,P=0.000),抑癌基因LRIG1、p16、eIF4E3、NDRG4、RASSF2A、Ebp1和侵袭基因TIMP1、E-cadherin的mRNA表达量显著高于对照组(t=19.018、18.706、16.997、20.411、25. 332、20.446、22.476、20. 289,P=0. 000)。结论术前新辅助化疗能够抑制宫颈癌病灶内促增殖分子及促侵袭基因的表达,促进抑癌基因及侵袭抑制基因的表达。
Objective To study the effect of preoperative neoadjuvant chemotherapy on the expression of malignant molecules in the resected lesions of patients with cervical cancer. Methods One hundred and eighteen patients with stage I b2 and stage II a2 cervical cancer diagnosed by Obstetrics and Gynecology Department of Xiaolan Hospital Affiliated to Southern Medical University from March 2015 to June 2017 were selected. They were randomly divided into two groups, 59 patients in each group. The experimental group received neoadjuvant chemotherapy combined with surgical resection, while the control group received surgical resection directly. Surgical resection of cervical cancer tissue, determination of proliferative molecules[Ki-67, human cell cycle related kinase(CCRK), cyclin B1(CyclinBl), cyclin-dependent kinase 1(CDK1), Polo-like kinase 1(Plkl), Survivin], tumor suppressor gene [polyleucine repeat region immunoglobulin-like protein 1(LRIG1),p16 gene, eukaryotic initiation factor 4 E3(eIF4 E3), N myc downstream regulatory gene 4(NDRG4)), Ras-related domain factor 2 A(RASSF2 A), enhancer-binding protein 1(Ebp1), and invasive genes [ β catenin(beta catenin), matrix metalloproteinase 8( MMP8), disintegrin-metalloproteinase 19(Expression levels of ADAM19), tissue inhibitor of metalloproteinase-1(TIMP1), and E cadherin. Results The expression of Ki-67, CCRK, CyclinBl, CDK1, Plkl, Survivin and beta catenin,MMP8 and ADAM19 in cervical cancer lesions of the experimental group was significantly lower than that of the control group(t=22.019, t=26.009, t = 15.096, t=21.991, t=26.727, t=14.592, t=14.309, t=21.111, t=18. 154, P=0.000), and the expression levels of tumor suppressor genes LRIG1, p16, eIF4 E3, NDRG4, RASSF2 A, Ebpl and invasive genes TIMP1, E cadherin were significantly higher than those of the control group(t=19.018, t = 18.706, t=16.997, t =20.411, t = 25. 332, t =20.446, t =22.476, t = 20.289, P = 0.000). Conclusion Preoperative neoadjuvant chemotherapy can inhibit the expression of proliferative molecules and invasive genes in cervical cancer lesions, and promote the expression of tumor suppressor genes and invasive suppressor genes.
Objective To study the effect of preoperative neoadjuvant chemotherapy on the expression of malignant molecules in the resected lesions of patients with cervical cancer. Methods One hundred and eighteen patients with stage I b2 and stage II a2 cervical cancer diagnosed by Obstetrics and Gynecology Department of Xiaolan Hospital Affiliated to Southern Medical University from March 2015 to June 2017 were selected. They were randomly divided into two groups, 59 patients in each group. The experimental group received neoadjuvant chemotherapy combined with surgical resection, while the control group received surgical resection directly. Surgical resection of cervical cancer tissue, determination of proliferative molecules[Ki-67, human cell cycle related kinase(CCRK), cyclin B1(CyclinBl), cyclin-dependent kinase 1(CDK1), Polo-like kinase 1(Plkl), Survivin], tumor suppressor gene [polyleucine repeat region immunoglobulin-like protein 1(LRIG1),p16 gene, eukaryotic initiation factor 4 E3(eIF4 E3), N myc downstream regulatory gene 4(NDRG4)), Ras-related domain factor 2 A(RASSF2 A), enhancer-binding protein 1(Ebp1), and invasive genes [ β catenin(beta catenin), matrix metalloproteinase 8( MMP8), disintegrin-metalloproteinase 19(Expression levels of ADAM19), tissue inhibitor of metalloproteinase-1(TIMP1), and E cadherin. Results The expression of Ki-67, CCRK, CyclinBl, CDK1, Plkl, Survivin and beta catenin,MMP8 and ADAM19 in cervical cancer lesions of the experimental group was significantly lower than that of the control group(t=22.019, t=26.009, t = 15.096, t=21.991, t=26.727, t=14.592, t=14.309, t=21.111, t=18. 154, P=0.000), and the expression levels of tumor suppressor genes LRIG1, p16, eIF4 E3, NDRG4, RASSF2 A, Ebpl and invasive genes TIMP1, E cadherin were significantly higher than those of the control group(t=19.018, t = 18.706, t=16.997, t =20.411, t = 25. 332, t =20.446, t =22.476, t = 20.289, P = 0.000). Conclusion Preoperative neoadjuvant chemotherapy can inhibit the expression of proliferative molecules and invasive genes in cervical cancer lesions, and promote the expression of tumor suppressor genes and invasive suppressor genes.
引文
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[11] Tay TKY,Lim KL,Hilmy MH,et al. Comparison of the sensitivity and specificity of p16/Ki-67 dual staining and HPV DNA testing of abnormal cervical cytology in the detection of histology proven cervical intraepithelial neoplasia grade 2 and above(CIN 2+)[J]. Malays J Pathol,2017,39(3):257-265.
[12]Pang T,Wang S,Gao M,et al. HPV18 E7 induces the over-transcription of eIF4E gene in cervical cancer[J]. Iran J Basic Med Sci,2015,18(7):684-690.
[13] Asimomytis A,Karanikou M,Rodolakis A,et al. mTOR downstream effectors,4EBP1 and eIF4E,are overexpressed and associated with HPV status in precancerous lesions and carcinomas of the uterine cervix[J]. Oncol Lett,2016,12(5):3234-3240. DOI:10. 3892/ol.2016.5056.(下转66页)
[14] Zhang X,Ma Y, Wu Y,et al. Aberrant promoter methylation and silencing of RASSF2A gene in cervical cancer[J]. J Obstet Gynaecol Res,2014,40(5):1375-1381.
[15] Liu L,Li XD,Chen HY,et al. Significance of Ebpl and p53 protein expression in cervical cancer[J].Genet Mol Res, 2015,14(4):11860-11866. DOI:10.1111/jog. 12322
[16] Liu L, Xu DY, Yang SS, et al. Ebpl protein expression in cervical cancer tissue and its significance[J]. Genet Mol Res,2015,14(2):5496-5500. DOI:10.4238/2015. May. 22.20
[17] Sun X,Liu Y. Activation of the Wnt/β-catenin signaling pathway may contribute to cervical cancer pathogenesis via upregulation of Twist[J]. Oncol Lett,2017,14(4):4841-4844. DOI:10. 3892/ol.2017.6754
[18] Chang YH, Chu TY, Ding DC. WNT/β-Catenin signaling pathway regulates non-tumorigenesis of human embryonic stem cells co-cultured with human umbilical cord mesenchymal stem cells[J]. Sci Rep,2017,3(7):1~10. DOI:10.1038/srep41913
[19] Qureshi R,Arora H,Rizvi MA. EMT in cervical cancer:its role in tumour progression and response to therapy[J]. Cancer Lett,2015,356(2 Pt B):321-331. DOI:10.1016/j. canlet.2014. 09.021
[20] Zhu X,Li Y,Zhou R,et al. Knockdown of E-cadherin expression of endometrial epithelial cells may activate Wnt/β-cateninpathway in vitro[J]. Arch Gynecol Obstet,2018,297(I):117-123. DOI:10.1007/s00404-017-4560-0
[2] Chen Z,Shi Y,Wang S,et al. Meta-analysis showing that early response to neoadjuvant chemotherapy predicts better survival among cervical cancer patients[J]. Oncotarget, 2017, 8(35):59609-59617. DOI:10.18632/oncotarget. 19425
[3] De Azevedo CRAS,Thuler LCS,De Mello MJG,et al. Phase II trial of neoadjuvant chemotherapy followed by chemoradiation in locally advanced cervical cancer[J]. Gynecol Oncol,2017,146(3):560-565.DOI:10. 1016/j. ygyno.2017.07.006
[4] Salihi R,Leunen K,Moerman P,et al. Neoadjuvant weekly paclitaxel-carboplatin is effective in stageⅠ-Ⅱcervical cancer[J]. Int J Gynecol Cancer, 2017, 27(6):1256-1260. DOI:10. 1097/IGC.0000000000001021
[5]李雪,孔为民,韩超,等.Ib2和IIa2期子宫颈癌患者以手术为主的不同治疗方案的前瞻性随机对照研究[J].中华妇产科杂志,2016,51(7):524-529. DOI:10. 3760/cma. j. issn. 0529-567x.2016.07.008
[6] Wang HR,Li YC,Guo HQ,et al. A cocktail of P16INK4a and Ki-67,P16~(INK4a)and minichromosome maintenance protein 2 as triage tests for human papillomavirus primary cervical cancer screening[J]. Oncotarget,2017,8(48):83890-83899. DOI:10. 18632/oncotarget.19870
[7]郑健,王琨.CyclinB1、HPV16蛋白在宫颈组织芯片中的表达及临床意义[J].中国老年学杂志,2016,36(5):1050-1052. DOI:10.3969/j. issn. 1005-9202.2016.05.012
[8] Liu HQ, Wang YH,Wang LL,et al. P16INK4A and survivin:Diagnostic and prognostic markers in cervical intraepithelial neoplasia and cervical squamous cell carcinoma[J]. Exp Mol Pathol,2015,99(1):44-49. DOI:10.1016/j. yexmp. 2015.04.004
[9] Guo L,Zhang W,Sheng Y,Chen K,Shi Q,Zhang P,et al. Expression and significance of LRIG3 in human cervical squamous cell carcinoma[J].Eur J Gynaecol Oncol,2015,36(4):414-419.
[10]Xing Y,Wang C,Wu J. Expression of geminin,p16,and Ki67 in cervical intraepithelial neoplasm and normal tissues[J]. Medicine(Baltimore),2017,96(26):e7302. DOI:10.1097/MD.0000000000007302
[11] Tay TKY,Lim KL,Hilmy MH,et al. Comparison of the sensitivity and specificity of p16/Ki-67 dual staining and HPV DNA testing of abnormal cervical cytology in the detection of histology proven cervical intraepithelial neoplasia grade 2 and above(CIN 2+)[J]. Malays J Pathol,2017,39(3):257-265.
[12]Pang T,Wang S,Gao M,et al. HPV18 E7 induces the over-transcription of eIF4E gene in cervical cancer[J]. Iran J Basic Med Sci,2015,18(7):684-690.
[13] Asimomytis A,Karanikou M,Rodolakis A,et al. mTOR downstream effectors,4EBP1 and eIF4E,are overexpressed and associated with HPV status in precancerous lesions and carcinomas of the uterine cervix[J]. Oncol Lett,2016,12(5):3234-3240. DOI:10. 3892/ol.2016.5056.(下转66页)
[14] Zhang X,Ma Y, Wu Y,et al. Aberrant promoter methylation and silencing of RASSF2A gene in cervical cancer[J]. J Obstet Gynaecol Res,2014,40(5):1375-1381.
[15] Liu L,Li XD,Chen HY,et al. Significance of Ebpl and p53 protein expression in cervical cancer[J].Genet Mol Res, 2015,14(4):11860-11866. DOI:10.1111/jog. 12322
[16] Liu L, Xu DY, Yang SS, et al. Ebpl protein expression in cervical cancer tissue and its significance[J]. Genet Mol Res,2015,14(2):5496-5500. DOI:10.4238/2015. May. 22.20
[17] Sun X,Liu Y. Activation of the Wnt/β-catenin signaling pathway may contribute to cervical cancer pathogenesis via upregulation of Twist[J]. Oncol Lett,2017,14(4):4841-4844. DOI:10. 3892/ol.2017.6754
[18] Chang YH, Chu TY, Ding DC. WNT/β-Catenin signaling pathway regulates non-tumorigenesis of human embryonic stem cells co-cultured with human umbilical cord mesenchymal stem cells[J]. Sci Rep,2017,3(7):1~10. DOI:10.1038/srep41913
[19] Qureshi R,Arora H,Rizvi MA. EMT in cervical cancer:its role in tumour progression and response to therapy[J]. Cancer Lett,2015,356(2 Pt B):321-331. DOI:10.1016/j. canlet.2014. 09.021
[20] Zhu X,Li Y,Zhou R,et al. Knockdown of E-cadherin expression of endometrial epithelial cells may activate Wnt/β-cateninpathway in vitro[J]. Arch Gynecol Obstet,2018,297(I):117-123. DOI:10.1007/s00404-017-4560-0