陈茜,王海燕,刘宪,刘佳
CHEN Qian,WANG Haiyan,LIU Xian,LIU Jia

• 1:西安交通大学第一附属医院生殖医学科
• 2:陕西省肿瘤医院胸外科

摘要(Abstract)：

目的 探讨EZH2在宫颈癌中对顺铂耐药的作用及机制。方法 将宫颈癌细胞分为对照组+干扰EZH2(shRNA)组、对照组+过表达EZH2组、对照组+GSK343处理组及对照组+顺铂(DDP)耐药组，采用MTT法检测细胞耐药性，实时荧光定量PCR检测EZH2、ABCG2 mRNA表达水平，蛋白印迹法检测EZH2、ABCG2蛋白表达情况。结果 与对照组比较，干扰EZH2组顺铂IC50降低，细胞抑制率升高，ABCG2 mRNA和蛋白表达降低；过表达EZH2组顺铂IC50升高，细胞抑制率降低，ABCG2 mRNA和蛋白表达升高；GSK343处理组顺铂IC50降低，细胞抑制率升高；与对照组比较，顺铂耐药组EZH2、ABCG2的mRNA和蛋白表达升高，差异均有统计学意义(P<0.05)。结论 EZH2诱导人宫颈癌细胞对顺铂的耐药，其机制可能与调控细胞耐药相关基因ABCG2的表达有关。
Objective To investigate the role and regulatory mechanism of EZH2 gene in cisplatin resistance in cervical cancer. Methods Cervical cancer cells were divided into the control group+interference EZH2(shRNA) group, the control group+overexpression EZH2 group, the control group+GSK343 treatment group and the control group+cisplatin(DDP) resistance group. The drug resistance of cells was detected by MTT method. The mRNA expression levels of EZH2 and ABCG2 were detected by real-time fluorescence quantitative PCR, and the protein expression of EZH2 and ABCG2 were detected by protein printing. Results Compared with the control group, the cisplatin IC50 decreased, the cell inhibition rate increased, and the expression of ABCG2 mRNA and protein decreased in the EZH2 interference group. In EZH2 overexpression group, cisplatin IC50 increased, the cell inhibition rate decreased, and the expression of ABCG2 mRNA and protein increased. Cisplatin IC50 decreased and cell inhibition rate increased in GSK343 treatment group. Compared with the control group, the mRNA and protein expressions of EZH2 and ABCG2 in cisplatin resistance group were significantly higher, and the differences were statistically significant(P<0.05). Conclusion EZH2 can induce cisplatin resistance in human cervical cancer cells, and its mechanism may be related to the regulation of the expression of drug resistance related gene ABCG2.

关键词(KeyWords)： 宫颈肿瘤;基因;EZH2;顺铂;耐药性;蛋白表达
cervical cancer;gene;EZH2;cisplatin;drug-resistance;protein expression

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金[2017]81702579;; 陕西省肿瘤医院院基金(SC211004)

作者(Author): 陈茜,王海燕,刘宪,刘佳
CHEN Qian,WANG Haiyan,LIU Xian,LIU Jia

DOI: 10.19367/j.cnki.2096-8388.2023.07.005

参考文献(References)：

• [1] OLUSOLA P,BANERJEE H N,PHILLEV J V,et al.Human papilloma virus-associated cervical cancer and health disparities[J].Cells,2019,8(6):622.
• [2] HU Z,MA D.The precision prevention and therapy of HPV-related cervical cancer:new concepts and clinical implications[J].Cancer Medicine,2018,7(10):5217-5236.
• [3] 王黎明，汪辉.宫颈癌化疗策略及进展[J].中国实用妇科与产科杂志，2019,35(10):27-30.
• [4] SAFAEI S,BARADARAN B,HAGH M F,et al.Double sword role of EZH2 in leukemia[J].Biomedecine & Pharmacotherapie,2018,98(7):626-635.
• [5] WEN Y,HOU Y,YI X,et al.EZH2 activates CHK1 signaling to promote ovarian cancer chemoresistance by maintaining the properties of cancer stem cells[J].Theranostics,2021,11(4):1795-1813.
• [6] WANG J,WANG G G.No easy way out for EZH2:its pleiotropic,noncanonical effects on gene regulation and cellular function[J].International Journal of Molecular Sciences,2020,21(24):9501.
• [7] CHEN S,YAO F,XIAO Q,et al.EZH2 inhibition sensitizes tamoxifenresistant breast cancer cells through cell cycle regulation[J].Molecular Medicine Reports,2018,17(2):2642-2650.
• [8] CHEN Q,ZHENG P S,YANG W T.EZH2-mediated repression of GSK-3β and TP53 promotes Wnt/β-catenin signaling-dependent cell expansion in cervical carcinoma[J].Oncotarget,2016,7(24):36115-36129.
• [9] CAO H Z,LIU X F,YANG W T,et al.LGR5 promotes cancer stem cell traits and chemoresistance in cervical cancer[J].Cell Death & Disease,2017,8(9):e3039.
• [10]JUNG J,KIM S,AN H T,et al.α-actinin-4 regulates cancer stem cell properties and chemoresistance in cervical cancer[J].Carcinogenesis,2020,41(7):940-949.
• [11]YU M,XU B,YANG H,et al.MicroRNA-218 regulates the chemo-sensitivity of cervical cancer cells through targeting survivin[J].Cancer Management and Research,2019,11:6511-6519.
• [12]CHEN X,XIONG D,YE L,et al.SPP1 inhibition improves the cisplatin chemo-sensitivity of cervical cancer cell lines[J].Cancer Chemotherapy and Pharmacology,2019,83(4):603-613.
• [13]LI Z,LI M,WANG D,et al.Post-translational modifications of EZH2 in cancer[J].Cell and Bioscience,2020,10(1) :143.
• [14]GAUTAM N,KAUR M,KAUR S.Structural assembly of polycomb group protein and Insight of EZH2 in cancer progression:a review[J].Journal of Cancer Research and Therapeutics,2020,17(2):311-326.
• [15]RINKE J,CHASE A,CROSS N C P,et al.EZH2 in myeloid malignancies[J].Cells,2020,9(7):1639.
• [16]LIM H J,KIM M.EZH2 as a potential target for NAFLD therapy[J].International Journal of Molecular Sciences,2020,21(22):8617.
• [17]QIU Z,ZHU W,MENG H,et al.CDYL promotes the chemoresistance of small cell lung cancer by regulating H3K27 trimethylation at the CDKN1C promoter[J].Theranostics,2019,9(16):4717-4729.
• [18]HU J,ZHANG J,SUN F,et al.Enhancer of zeste 2 polycomb repressive complex 2 subunit promotes sorafenib resistance of hepatocellular carcinoma though insulin-like growth factor 1 receptor[J].Anti-Cancer Drugs,2019,30(7):e0746.
• [19]TAHERI M,SHOOREI H,ANAMAG F T,et al.LncRNAs and miRNAs participate in determination of response of cancer cells to cisplatin[J].Experimental and Molecular Pathology,2021:104602.
• [20]KATHAWALA R J,ESPITIA C M,JONES T M,et al.ABCG2 overexpression contributes to pevonedistat resistance[J].Cancers,2020,12(2):429.
• [21]LIU C,XING W,YU H,et al.ABCB1 and ABCG2 restricts the efficacy of gedatolisib (PF-05212384),a PI3K inhibitor in colorectal cancer cells[J].Cancer Cell International,2021,21(1) :108.
• [22]HUO Q,YUAN J,ZHU T,et al.A combined bioinformatic and nanoparticle-based study reveal the role of ABCG2 in the resistance of breast cancer[J].Recent Patents on Anti-Cancer Drug Discovery,2021,16(1):57-62.

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