赖氨酸特异性脱甲基酶2B及B细胞淋巴瘤-2蛋白、Hrk蛋白在卵巢癌组织中的表达情况及其临床意义
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摘要
目的分析赖氨酸特异性脱甲基酶2B(KDM2B)、B细胞淋巴瘤-2(Bcl-2)蛋白、Hrk蛋白在卵巢癌中的表达情况及其临床意义。方法收集20例正常卵巢组织、30例良性卵巢肿瘤组织以及50例恶性卵巢肿瘤组织。采用免疫组织化学法检测3种组织KDM2B、Bcl-2蛋白、Hrk蛋白的表达情况。比较不同临床病理特征的恶性卵巢肿瘤患者间3种蛋白表达的情况,并分析恶性卵巢肿瘤组织中3种蛋白表达的相关性。结果恶性卵巢肿瘤组织的KDM2B、Bcl-2蛋白阳性表达率高于良性卵巢肿瘤组织及正常卵巢组织(均P <0.05),恶性卵巢肿瘤组织、良性卵巢肿瘤组织、正常卵巢组织的Hrk阳性表达率依次升高(均P <0. 05)。低分化、国际妇产科联合会(FIGO)分期Ⅲ～Ⅳ期、淋巴结转移病例的KDM2B及Bcl-2蛋白阳性表达率均分别高于中-高分化、FIGO分期Ⅰ～Ⅱ期、无淋巴结转移病例(均P <0. 05),而Hrk蛋白阳性表达率均分别低于中-高分化、FIGO分期Ⅰ～Ⅱ期、无淋巴结转移病例(均P <0. 05)。不同年龄段病例的3种蛋白阳性表达率比较,差异均无统计学意义(均P> 0. 05)。在卵巢恶性肿瘤组织中,KDM2B、Bcl-2蛋白与Hrk蛋白的阳性表达率均呈负相关(均P <0. 05)。结论卵巢癌中KDM2B与Bcl-2蛋白的表达上调,Hrk蛋白的表达下调,三者可能通过不同的方式参与卵巢癌的发生发展。
Objective To analyze the expression and clinical significance of lysine( K)-specific demethylase2 B( KDM2 B),B-cell lymphoma-2( Bcl-2) protein,and Hrk protein in ovarian cancer tissues. Methods Twenty specimens of normal ovarian tissues,30 specimens of benign ovarian tumor tissues and 50 specimens of malignant ovarian tumor tissues were collected. The expression of KDM2 B,Bcl-2 protein and Hrk protein from the three kinds of tissues were detected using immunohistochemistry assay. The expression of the three proteins were compared among patients with malignant ovarian tumors of different clinicopathological features,and the correlation among the three proteins expression in malignant ovarian tumor tissues was analyzed. Results The positive expression rates of KDM2 B and Bcl-2 protein in malignant ovarian tumor tissues were higher than those in benign ovarian tumor tissues or normal ovarian tissues( all P < 0. 05),the positive expression rate of Hrk protein increased in the order of malignant ovarian tumor tissues,benign ovarian tumor tissues,and normal ovarian tissues( all P < 0. 05). Patients with poor differentiation,with International Federation of Gynecology and Obstetrics( FIGO) stage Ⅲ-Ⅳ,or with lymphatic metastasis had higher positive expression rates of KDM2 B and Bcl-2 protein,along with lower positive expression rate of Hrk protein,than those with moderate-well differentiation,with FIGO stage Ⅰ-Ⅱ,or without lymphatic metastasis,respectively( all P < 0. 05). The positive expression rates of the three proteins showed no statistically significant differences among cases of various age groups( all P > 0. 05). In malignant ovarian tumor tissues,the positive expression rate of KDM2 B or Bcl-2 protein negatively correlated with the positive rate of Hrk protein( all P < 0. 05). Conclusion Up-regulation of KDM2 B and Bcl-2 protein,and down-regulation of Hrk protein are observed in ovarian cancer,the three proteins probably participate in the occurrence and development of ovarian cancer via various ways.
Objective To analyze the expression and clinical significance of lysine( K)-specific demethylase2 B( KDM2 B),B-cell lymphoma-2( Bcl-2) protein,and Hrk protein in ovarian cancer tissues. Methods Twenty specimens of normal ovarian tissues,30 specimens of benign ovarian tumor tissues and 50 specimens of malignant ovarian tumor tissues were collected. The expression of KDM2 B,Bcl-2 protein and Hrk protein from the three kinds of tissues were detected using immunohistochemistry assay. The expression of the three proteins were compared among patients with malignant ovarian tumors of different clinicopathological features,and the correlation among the three proteins expression in malignant ovarian tumor tissues was analyzed. Results The positive expression rates of KDM2 B and Bcl-2 protein in malignant ovarian tumor tissues were higher than those in benign ovarian tumor tissues or normal ovarian tissues( all P < 0. 05),the positive expression rate of Hrk protein increased in the order of malignant ovarian tumor tissues,benign ovarian tumor tissues,and normal ovarian tissues( all P < 0. 05). Patients with poor differentiation,with International Federation of Gynecology and Obstetrics( FIGO) stage Ⅲ-Ⅳ,or with lymphatic metastasis had higher positive expression rates of KDM2 B and Bcl-2 protein,along with lower positive expression rate of Hrk protein,than those with moderate-well differentiation,with FIGO stage Ⅰ-Ⅱ,or without lymphatic metastasis,respectively( all P < 0. 05). The positive expression rates of the three proteins showed no statistically significant differences among cases of various age groups( all P > 0. 05). In malignant ovarian tumor tissues,the positive expression rate of KDM2 B or Bcl-2 protein negatively correlated with the positive rate of Hrk protein( all P < 0. 05). Conclusion Up-regulation of KDM2 B and Bcl-2 protein,and down-regulation of Hrk protein are observed in ovarian cancer,the three proteins probably participate in the occurrence and development of ovarian cancer via various ways.
引文
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[12]李敏,夏永华,刘冬,等.葡萄糖6磷酸脱氢酶表达下调对皮肤鳞癌细胞系A431细胞凋亡和侵袭能力的影响[J].中华病理学杂志,2016,45(1):49-50.
[13]吴琼,王小中.急性白血病患者外周血CD4+CD25+Foxp3+调节性T细胞检测及其对细胞凋亡的作用[J].实验与检验医学,2017,35(3):304-307.
[14] Merino D,Lok SW,Visvader JE,et al. Targeting BCL-2 to enhance vulnerability to therapy in estrogen receptor-positive breast cancer[J]. Oncogene,2016,35(15):1 877-1 887.
[15] Stein MN,Hussain M,Stadler WM,et al. A phaseⅡstudy of AT-101 to overcome Bcl-2 mediated resistance to androgen deprivation therapy in patients with newly diagnosed castration sensitive metastatic prostate cancer[J]. Clin Genitourin Cancer,2016,14(1):22-27.
[16] Cheng X,Liu Q,Li H,et al. Lipid nanoparticles loaded with an antisense oligonucleotide gapmer against Bcl-2 for treatment of lung cancer[J]. Pharm Res,2017,34(2):310-320.
[17]黄娟. Bcl-2、Bax蛋白在皮肤鳞状细胞癌组织中的表达水平变化及与病理学特征的关系[J].实验与检验医学,2018,36(5):648-650.
[18]金向东,何旭华,叶盛威,等. miR-16通过调节Bcl-2的表达活性影响胃癌细胞的生物学行为[J].西部医学,2018,30(11):1 573-1 578.
[19] Puthalakath H,Strasser A. Keeping killers on a tight leash:transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins[J]. Cell Death Differ,2002,9(5):505-512.
[20] Inohara N,Ding L,Chen S,et al. Harakiri,a novel regulator of cell death,encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2and Bcl-XL[J]. EMBO,1997,16(7):1 686-1 694.
[21] Chang I,Majid S,Saini S,et al. Hrk mediates 2-methoxyestradiol-induced mitochondrial apoptotic signaling in prostate cancer cells[J]. Mol Cancer Ther,2013,12(6):1 049-1 059.
[22] Li H,Cai Q,Wu H,et al. SUZ12 promotes human epithelial ovarian cancer by suppressing apoptosis via silencing HRK[J].Mol Cancer Res,2012,10(11):1 462-1 472.
[23]赵文江,周喜元,潘杰锋,等. Bcl-2和Hrk及Cyclin E基因在胃癌组织中的表达及其意义[J].中华临床医师杂志,2012,18(6):5 676-5 679.
[24] Wang Y,Zang J,Zhang D,et al. KDM2B overexpression correlates with poor prognosis and regulates glioma cell growth[J].Onco Targets Ther,2018,11:201-209.
[25] Zaker F,Amirizadeh N,Nasiri N. Gene expression and methylation patter in HRK apoptotic gene in myelodysplastic syndrome[J]. Int J Mol Cell Med,2016,5(2):90-99.
[26] Karoopongse E,Yeung C,Byon J,et al. The KDM2B-Let-7bEZH2 axis in myelodysplastic syndromes as a target for combined epigenetic therapy[J]. PLo S One,2014,169(9):e107817.
[2]沈旭霞,喻林,毕蕊,等.卵巢低、高级别浆液性癌的临床病理分析及Pax2、p53和Ki-67表达的意义[J].中华病理学杂志,2011,40(8):511-516.
[3] Siegel RL,Miller KD,Jemal A. Cancer statistics,2015[J].CA Cancer J Clin,2015,65(1):5-29.
[4]王晓玲,董莹莹,蒋靖志.卵巢癌组织中Oct-4与Sox-2的表达及意义[J].解剖学研究,2018,40(6):501-504.
[5] Tsukada Y,Fang J,Erdjument-Bromage H,et al. Histone demethylation by a family of Jmj C domain-containing proteins[J]. Nature,2006,439(7 078):811-816.
[6] Long HK,Blackledge NP,Klose RJ. ZF-CxxC domain-containing proteins,Cp G islands and the chromatin connection[J].Biochem Soc Trans,2013,41(3):727-740.
[7] Andricovich J,Kai Y,Peng W,et al. Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis[J]. J Clin Invest,2016,126(3):905-920.
[8] Leonard A,Wolff JE. Etoposide improves survival in highgrade glioma:a meta-analysis[J]. Anticancer Res,2013,33(8):3 307-3 315.
[9] Zhao E,Tang C,Jiang X,et al. Inhibition of cell proliferation and induction of autophagy by KDM2B/FBXL10 knockdown in gastric cancer cells[J]. Cell Signal,2017,36:222-229.
[10] Tzatsos A,Paskaleva P,Ferrari F,et al. KDM2B promotes pancreatic cancer via Polycomb-dependent and-independent transcriptional programs[J]. J Clin Invest,2013,123(2):727-739.
[11] Kuang Y,Lu F,Guo J,et al. Histone demethylase KDM2B upregulates histone methyltransferase EZH2 expression and contributes to the progression of ovarian cancer in vitro and in vivo[J]. Onco Targets Ther,2017,10:3 131-3 144.
[12]李敏,夏永华,刘冬,等.葡萄糖6磷酸脱氢酶表达下调对皮肤鳞癌细胞系A431细胞凋亡和侵袭能力的影响[J].中华病理学杂志,2016,45(1):49-50.
[13]吴琼,王小中.急性白血病患者外周血CD4+CD25+Foxp3+调节性T细胞检测及其对细胞凋亡的作用[J].实验与检验医学,2017,35(3):304-307.
[14] Merino D,Lok SW,Visvader JE,et al. Targeting BCL-2 to enhance vulnerability to therapy in estrogen receptor-positive breast cancer[J]. Oncogene,2016,35(15):1 877-1 887.
[15] Stein MN,Hussain M,Stadler WM,et al. A phaseⅡstudy of AT-101 to overcome Bcl-2 mediated resistance to androgen deprivation therapy in patients with newly diagnosed castration sensitive metastatic prostate cancer[J]. Clin Genitourin Cancer,2016,14(1):22-27.
[16] Cheng X,Liu Q,Li H,et al. Lipid nanoparticles loaded with an antisense oligonucleotide gapmer against Bcl-2 for treatment of lung cancer[J]. Pharm Res,2017,34(2):310-320.
[17]黄娟. Bcl-2、Bax蛋白在皮肤鳞状细胞癌组织中的表达水平变化及与病理学特征的关系[J].实验与检验医学,2018,36(5):648-650.
[18]金向东,何旭华,叶盛威,等. miR-16通过调节Bcl-2的表达活性影响胃癌细胞的生物学行为[J].西部医学,2018,30(11):1 573-1 578.
[19] Puthalakath H,Strasser A. Keeping killers on a tight leash:transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins[J]. Cell Death Differ,2002,9(5):505-512.
[20] Inohara N,Ding L,Chen S,et al. Harakiri,a novel regulator of cell death,encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2and Bcl-XL[J]. EMBO,1997,16(7):1 686-1 694.
[21] Chang I,Majid S,Saini S,et al. Hrk mediates 2-methoxyestradiol-induced mitochondrial apoptotic signaling in prostate cancer cells[J]. Mol Cancer Ther,2013,12(6):1 049-1 059.
[22] Li H,Cai Q,Wu H,et al. SUZ12 promotes human epithelial ovarian cancer by suppressing apoptosis via silencing HRK[J].Mol Cancer Res,2012,10(11):1 462-1 472.
[23]赵文江,周喜元,潘杰锋,等. Bcl-2和Hrk及Cyclin E基因在胃癌组织中的表达及其意义[J].中华临床医师杂志,2012,18(6):5 676-5 679.
[24] Wang Y,Zang J,Zhang D,et al. KDM2B overexpression correlates with poor prognosis and regulates glioma cell growth[J].Onco Targets Ther,2018,11:201-209.
[25] Zaker F,Amirizadeh N,Nasiri N. Gene expression and methylation patter in HRK apoptotic gene in myelodysplastic syndrome[J]. Int J Mol Cell Med,2016,5(2):90-99.
[26] Karoopongse E,Yeung C,Byon J,et al. The KDM2B-Let-7bEZH2 axis in myelodysplastic syndromes as a target for combined epigenetic therapy[J]. PLo S One,2014,169(9):e107817.