TUBB3、ERCC1和P-gp在卵巢癌中的表达及其临床意义

发布时间：2018-04-25 04:34

  本文选题：卵巢癌 + 抗微管　； 参考：《承德医学院》2014年硕士论文

【摘要】：卵巢癌(ovarian cancer,OC)是妇科常见的恶性肿瘤之一，在我国卵巢癌的发病率有上升趋势，居妇科肿瘤的第二位[1]，同时年龄趋于年轻化。卵巢癌发病较隐匿，大多数确诊时已属中晚期，五年生存率虽然逐渐升高，但是至今仍不到50%，可见卵巢癌是严重威胁女性健康的重大疾病之一。目前卵巢癌的治疗有手术、化疗及放疗等方法，而化疗在治疗卵巢癌中占有重要的地位。导致化疗失败并引起患者肿瘤复发、进展及死亡的主要原因是肿瘤细胞对化疗药物产生的多药耐药（multidrugresistance，MDR)。由多种基因、多因素和多步骤的复杂过程产生肿瘤耐药，而P-糖蛋白（P-glycoprotein，P-gp）是多药耐药基因MDR1编码产物，产生多药耐药性的主要原因是P-gp高表达，而P-gp耐药机制是在临床实践中唯一得到证实的，解决此障碍，肿瘤化疗效果将取得突破性进展。治疗卵巢癌标准的化疗方案是紫杉类联合铂类，部分患者对紫杉类及铂类药物不敏感，效果不佳，如果卵巢癌患者对紫杉类、铂类药物敏感性好，有利于提高化疗有效率和延长患者生存期使之受益。因此探寻对铂类和紫杉类化疗敏感性的预测因子对指导临床合理用药非常重要。 TUBB3（class III beta-tubulin，β-微管蛋白III型)是细胞骨架的重要组成部分，在多种真核细胞和部分原核细胞中存在，能够维持细胞形态结构和参与细胞运动，还在细胞的生长、分裂、凋亡和信息传导中起着重要作用，而紫杉类药物可特异性的与β微管蛋白III结合可阻滞其解聚，阻止有丝分裂的完成，从而引起细胞凋亡达到杀灭肿瘤的作用。有研究表明TUBB3与紫杉类等抗微管类化疗药物的耐药密切相关，其高表达可以使紫杉类药物降低对微管蛋白的解聚，，从而导致其耐药。 核苷酸切除修复交叉互补基因1(excision repair cross-complementinggroup1，ERCC1)具有识别DNA损伤和链间切割的功能，是核苷酸剪切修复过程中最关键的一个内切酶，其过表达可使肿瘤细胞停滞在G2/M期，能够迅速修复损伤的DNA，引起对铂类药物耐药。 P-糖蛋白（P-glycoprotein，P-gp）是ATP依赖性跨膜蛋白，不仅可能量依赖性地将药物泵出细胞外，还能阻止化疗药物进入到细胞内从而减少细胞内的药物浓度；此外还可对细胞内的药物分布发生改变，把部分药物都聚集在不能产生自身作用的细胞器中，使药物达不到疗效，从而导致耐药。 目的: 通过检测TUBB3、ERCC1和P-gp在卵巢癌组织及正常卵巢组织中的表达，分析三者分别与卵巢癌患者相关临床病理因素之间的关系；探讨TUBB3、ERCC1和P-gp在卵巢癌中表达的相关性，预测卵巢癌患者对药物的敏感性及制定个体化治疗方案提供依据。 方法： 收集手术切除并经术后病理确诊的卵巢癌组织50例和正常卵巢组织(双附件无病理情况子宫肌瘤患者的手术切除卵巢为正常对照组)25例病理蜡块，将筛选出的50例卵巢癌患者的完整病例资料进行整理，术前均未接受化疗、放疗、生物免疫治疗。用免疫组织化学法Envision两步法检测TUBB3、ERCC1、P-gp在卵巢癌组织中的表达，分析其与患者年龄、组织学类型、病理分级、临床分期、肿瘤发生部位之间的关系；应用SPSS17.0统计软件处理数据，计数资料采用2检验，相关性采用Spearman相关分析，均以α=0.05作为检验标准，P＜0.05为差异有统计学意义。 结果： 免疫组织化学结果 1.TUBB3和ERCC1、P-gp在卵巢癌组织和正常卵巢组织中均有表达，TUBB3阳性表达定位于细胞浆，在卵巢癌组织表达阳性率为52.0%（26/50），正常卵巢组织中的阳性率表达为24.0%（6/25），显著高于正常卵巢组织中表达，差异有统计学意义（2=7.038，P=0.008）；ERCC1阳性表达定位于细胞核，在卵巢癌组织中表达阳性率为70.0%（35/50），正常卵巢组织中的阳性率表达为32.0%（8/25），卵巢癌组显著高于正常卵巢组，差异有统计学意义（2=9.420，P=0.002）；P-gp定位于细胞质或细胞膜中，在卵巢癌组织表达阳性率为85.0%（42/50)，正常卵巢组织中的阳性率表达为40.0%（10/25)，卵巢癌组显著高于正常卵巢组，差异有统计学意义（2=15.176，P=0.000）； 2.在蛋白质水平上卵巢癌组织中TUBB3、ERCC1和P-gp的表达与病理分级及临床分期有关（均P0.05)，其中肿瘤分期越晚三者的表达水平均越高，且在病理分级方面，亦是肿瘤分化程度越低表达水平越高，但三者与患者年龄、组织学类型、发生部位均无统计学差异（均P＞0.05）； 3.在卵巢癌组织中TUBB3和ERCC1的表达有相关性，且二者呈正相关，差异有统计学意义（P0.05）；TUBB3和P-gp在卵巢癌组织中的表达有相关性，且二者呈负相关，差异有统计学意义（P0.05）；卵巢癌组织中ERCC1的阳性表达率高于P-gp的表达，二者差异无统计学意义（P＞0.05），ERCC1表达与P-gp的表达无明显相关性。 结论： TUBB3、ERCC1和P-gp在卵巢癌组织中有较高的阳性表达率，在正常卵巢组织中低表达，提示三者均可能参与了卵巢癌的发生、发展过程，且三者在卵巢癌组织中的表达均与肿瘤病理分级及临床分期有关，病理分级越低、临床分期越晚表达的阳性率越高，提示三者与卵巢癌的发生、发展及肿瘤耐药有关；检测TUBB3和ERCC1在卵巢癌组织中的表达呈正相关；TUBB3和P-gp在卵巢癌组织中的表达呈负相关；ERCC1和P-gp在卵巢癌组织中表达无相关性。由于化疗耐药机制的复杂性，提示同时检测三者可能作为卵巢癌个体性化疗方案的制定、对化疗敏感性的重要指标。
[Abstract]:Ovarian cancer (ovarian cancer, OC) is one of the common malignant tumors in gynecology. The incidence of ovarian cancer is rising in our country. It is second [1] in gynecologic cancer, and the age tends to be younger. The incidence of ovarian cancer is more concealed. Most of the diagnosis of ovarian cancer is in the middle and late period. Although the five year survival rate is increasing gradually, it is still less than 50%, visible eggs are still visible. Cancer of the nests is one of the major diseases that seriously threaten the health of women. At present, the treatment of ovarian cancer has surgery, chemotherapy and radiotherapy, and chemotherapy plays an important role in the treatment of ovarian cancer. It leads to the failure of chemotherapy and causes the recurrence of the patients. The main cause of the progression and death is the multidrug resistance of the tumor cells to chemotherapeutic drugs (Multi Drugresistance, MDR). The complex process of multiple genes, multiple factors and multistep processes produces drug resistance, and P- glycoprotein (P-glycoprotein, P-gp) is the MDR1 encoding product of multidrug resistance gene. The main cause of multidrug resistance is the high expression of P-gp, and the mechanism of P-gp resistance is the only confirmed in clinical practice to solve this disorder. The therapeutic effect of tumor chemotherapy will make a breakthrough. The chemotherapy regimen for ovarian cancer is a combination of paclitaxel and platinum, some patients are not sensitive to Taxus and platinum drugs, and the effect is not good. If ovarian cancer patients have good sensitivity to Taxus and platinum drugs, it is beneficial to improve the efficiency of chemotherapy and to prolong the survival period of patients. Finding predictors of sensitivity to platinum and taxane chemotherapy is very important for guiding clinical rational use of drugs.
TUBB3 (class III beta-tubulin, beta microtubulin III) is an important component of the cytoskeleton. It exists in a variety of eukaryotic and partial prokaryotic cells. It can maintain cell morphology and participate in cell movement. It plays an important role in cell growth, division, apoptosis and information conduction, while Taxus drugs are specific. The combination of III with beta microtubule protein can block its depolymerization and prevent the completion of mitosis, causing apoptosis to kill the tumor. Studies have shown that TUBB3 is closely related to resistance to microtubule chemotherapeutic drugs such as Taxus, and its high expression can reduce the depolymerization of microtubule proteins by Taxus drugs and lead to their resistance.
Nucleotide excision repair cross complementary gene 1 (excision repair cross-complementinggroup1, ERCC1) has the function of identifying DNA damage and interchain cutting. It is the most critical endonuclease in the process of nucleotide shearing repair. Its overexpression can cause the tumor cells to stagnate in the G2/M phase, and can quickly repair the damaged DNA and cause the resistance to platinum drugs. Medicine.
P- glycoprotein (P-glycoprotein, P-gp) is a ATP dependent transmembrane protein that can not only pump out the drug out of the cell, but also prevent chemotherapeutic drugs from entering the cell and reduce the drug concentration in the cell. In addition, the distribution of drugs in the cells can be changed and some drugs can not produce their own effects. In organelles, drugs fail to achieve curative effect and lead to drug resistance.
Objective:
By detecting the expression of TUBB3, ERCC1 and P-gp in ovarian cancer tissue and normal ovarian tissue, the relationship between the three and the related clinicopathological factors of ovarian cancer patients was analyzed, and the correlation between TUBB3, ERCC1 and P-gp in ovarian cancer was discussed, and the sensitivity of the ovarian cancer patients to the drug was predicted and the individualized treatment scheme was provided. According to it.
Method锛

本文编号：1799794