胃癌组织中TPX2与肿瘤细胞铂类药物耐药的关系及意义
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摘要
目的检测胃癌组织、癌旁正常组织的Xklp2靶蛋白(targeting protein for Xklp2,TPX2)和耐药相关蛋白的表达,同时检测这些组织对顺铂(cisplatin,CDDP)、奥沙利铂(oxaliplatin,L-OHP)的敏感性,探讨TPX2在胃癌铂类药物耐药中的作用。方法收集85例手术切除的胃癌组织、30例癌旁正常组织的新鲜及石蜡标本;胃癌组织按术前接受新辅助治疗情况分为术前化疗组25例、术前未化疗组60例,癌旁正常组织30例。检测CDDP和L-OHP对3组细胞的抑制率以及CDDP和L-OHP对TPX2阳性者和TPX2阴性者细胞的抑制率,石蜡组织进行免疫组织化学染色,检测TPX2及P-糖蛋白(P-glycoprotein,P-gp)、谷胱甘肽S转移酶π(glutathione S transferase-π,GST-π)、B淋巴细胞/白血病2(B lymphatic leukaemia 2,Bcl-2)等耐药相关蛋白的表达。MTT法检测新鲜组织的细胞对CDDP、L-OHP的敏感性。结果 CDDP和L-OHP对3组细胞的抑制率比较,CDDP和L-OHP对术前化疗组和术前未化疗组的抑制率均低于癌旁正常组织,CDDP和L-OHP对术前化疗组细胞的抑制率又低于术前未化疗组(P<0.05);CDDP和L-OHP对胃癌患者中TPX2阳性者细胞的抑制率低于TPX2阴性者(P<0.05);术前化疗组和术前未化疗组TPX2、P-gp、GST-π和Bcl-2蛋白表达均高于癌旁正常组织,术前化疗组TPX2蛋白的表达又高于术前未化疗组(P<0.05)。结论 TPX2可通过调节耐药相关蛋白参与了胃癌耐药形成的过程,该蛋白的表达在化疗过程中发生了变化。
Objective To test expressions of targeting protein for Xklp2(TPX2) in gastric cancer and adjacent normal tissues, also chemosensitivity to cisplatin(CDDP), oxaliplatin(L-OHP), to investigate drug resistant related proteins, and to explore the effect of TPX2 in drug resistance of platinum-based drugs in gastric cancer. Methods The fresh tissues and paraffin specimens of 85 cases gastric cancer, 30 cases of adjacent normal tissues were collected. Tissues of cases gastric cancer were divided into chemotherapy group, non-chemotherapy group, and adjacent normal tissues group. Expressions of TPX2 and P-glycoprotein(P-gp), glutathione S transferase-π(GST-π), B lymphatic leukaemia 2(Bcl-2) were tested with immunohistochemistry. MTT assay was applied to detect chemosensitivity of fresh tissues in each group to CDDP, L-OHP. Results MTT assay showed that inhibition rates of CDDP, L-OHP to chemotherapy group, non-chemotherapy group were lower than adjacent normal tissues group, and inhibition rates of CDDP, L-OHP to chemotherapy group were lower than non-chemotherapy group(P<0.05). Inhibition rates of CDDP, L-OHP to positive TPX2 group were lower than negative TPX2 group(P<0.05). Positive rates of TPX2, P-gp, GST-π, Bcl-2 proteins in chemotherapy group, non-chemotherapy group were higher than that of adjacent normal tissues, and positive rates of these proteins in chemotherapy group were higher than that in non-chemotherapy group(P<0.05). Conclusion The TPX2 protein might be involved in drug resistance of gastric cancer by regulating some drug resistance related proteins, and expression of TPX2 changed in the process of chemotherapy.
Objective To test expressions of targeting protein for Xklp2(TPX2) in gastric cancer and adjacent normal tissues, also chemosensitivity to cisplatin(CDDP), oxaliplatin(L-OHP), to investigate drug resistant related proteins, and to explore the effect of TPX2 in drug resistance of platinum-based drugs in gastric cancer. Methods The fresh tissues and paraffin specimens of 85 cases gastric cancer, 30 cases of adjacent normal tissues were collected. Tissues of cases gastric cancer were divided into chemotherapy group, non-chemotherapy group, and adjacent normal tissues group. Expressions of TPX2 and P-glycoprotein(P-gp), glutathione S transferase-π(GST-π), B lymphatic leukaemia 2(Bcl-2) were tested with immunohistochemistry. MTT assay was applied to detect chemosensitivity of fresh tissues in each group to CDDP, L-OHP. Results MTT assay showed that inhibition rates of CDDP, L-OHP to chemotherapy group, non-chemotherapy group were lower than adjacent normal tissues group, and inhibition rates of CDDP, L-OHP to chemotherapy group were lower than non-chemotherapy group(P<0.05). Inhibition rates of CDDP, L-OHP to positive TPX2 group were lower than negative TPX2 group(P<0.05). Positive rates of TPX2, P-gp, GST-π, Bcl-2 proteins in chemotherapy group, non-chemotherapy group were higher than that of adjacent normal tissues, and positive rates of these proteins in chemotherapy group were higher than that in non-chemotherapy group(P<0.05). Conclusion The TPX2 protein might be involved in drug resistance of gastric cancer by regulating some drug resistance related proteins, and expression of TPX2 changed in the process of chemotherapy.
引文
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[2] Sun XP,Dong X,Lin L,et al.Up-regulation of survivin by AKT and hypoxia-inducible factor 1α contributes to cisplatin resistance in gastric cancer[J].FEBS J,2014,281(1):115-128.
[3] Zhao Q,Li Y,Tan BB,et al.HIF-1α induces multidrug resistance in gastric cancer cells by inducing MiR-27a[J].PLoS One,2015,10(8):e0132746.
[4] Liang B,Jia C,Huang Y,et al.TPX2 level correlates with hepatocellular carcinoma cell proliferation,apoptosis,and EMT[J].Dig Dis Sci,2015,60(8):2360-2372.
[5] Miwa T,Kokuryo T,Yokoyama Y,et al.Therapeutic potential of targeting protein for Xklp2 silencing for pancreatic cancer[J].Cancer Med,2015,4(7):1091-1100.
[6] Zhao YY,Yu L,Liu BL,et al.Downregulation of P-gp,Ras and p-ERK1/2 contributes to the arsenic trioxide-induced reduction in drug resistance towards doxorubicin in gastric cancer cell lines[J].Mol Med Rep,2015,12(5):7335-7343.
[7] 刘红春,李莹莹,刘玉含,等.食管鳞癌组织中TPX2 mRNA的表达及与临床病理生物学特征的关系[J].临床与实验病理学杂志,2010,26(2):151-153.
[8] 张春梅,李敏,周仕娴.乳腺癌组织中 TPX2 蛋白的表达及其临床意义[J].临床与实验病理学杂志,2015,31(5):528-531.
[9] 张红香,张云香,李湘洲,等.TPX2和胸苷磷酸化酶在胃癌中的表达及其临床意义[J].国际病理科学与临床杂志,2011,31(6):486-490.
[10] 才保加,祁玉娟,周为,等.结肠腺癌患者癌组织中TPX2、PTEN和Ki67的关系及临床意义[J].中国老年学杂志,2014,34(9):2399-2401.
[11] Chowdhury A,Chowdhury S,Tsai MY.A novel aurora kinase a inhibitor MK-8745 predicts TPX2 as a therapeutic biomarker in non-Hodgkin lymphoma cell lines[J].Leuk Lymphoma,2012,53(3):462-471.
[12] Gao Y,Shi W,Cui J,et al.Design,synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as P-glycoprotein-mediated multidrug resistance inhibitors [J].Bioorg Med Chem,2018,26(9):2420-2427.
[13] Geng M,Wang L,Chen X,et al.The association between chemosensitivity and Pgp,GST-π and Topo Ⅱ expression in gastric cancer[J].Diagn Pathol,2013,8:198.
[14] Phuthong S,Settheetham-Ishida W,Natphopsuk S,et al.Genetic polymorphism of the Glutathione S-transferase Pi 1(GSTP1) and susceptibility to cervical cancer in human papilloma virus infected northeastern thai women[J].Asian Pac J Cancer Prev,2018,19(2):381-385.
[15] 贾志宇,郭涛,庄志征,等.Bcl-2家族蛋白在莱菔硫烷诱导人涎腺腺样囊性癌细胞系ACC-M凋亡中的作用[J].河北医科大学学报,2016,37(2):161-165.
[16] 王颖欣,李昌英,何胜利.上皮性卵巢癌中Bcl-2/Bax比值与临床病理因素及化疗的关系[J].河北医科大学学报,2015,36(11):1282-1284,1299.