發(fā)布時間：2018-04-25 04:34

  本文選題：卵巢癌 + 抗微管��； 參考：《承德醫(yī)學(xué)院》2014年碩士論文

【摘要】：卵巢癌(ovarian cancer,OC)是婦科常見的惡性腫瘤之一，在我國卵巢癌的發(fā)病率有上升趨勢，居?jì)D科腫瘤的第二位[1]，同時年齡趨于年輕化。卵巢癌發(fā)病較隱匿，大多數(shù)確診時已屬中晚期，五年生存率雖然逐漸升高，但是至今仍不到50%，可見卵巢癌是嚴(yán)重威脅女性健康的重大疾病之一。目前卵巢癌的治療有手術(shù)、化療及放療等方法，而化療在治療卵巢癌中占有重要的地位。導(dǎo)致化療失敗并引起患者腫瘤復(fù)發(fā)、進(jìn)展及死亡的主要原因是腫瘤細(xì)胞對化療藥物產(chǎn)生的多藥耐藥（multidrugresistance，MDR)。由多種基因、多因素和多步驟的復(fù)雜過程產(chǎn)生腫瘤耐藥，而P-糖蛋白（P-glycoprotein，P-gp）是多藥耐藥基因MDR1編碼產(chǎn)物，產(chǎn)生多藥耐藥性的主要原因是P-gp高表達(dá)，而P-gp耐藥機(jī)制是在臨床實(shí)踐中唯一得到證實(shí)的，解決此障礙，腫瘤化療效果將取得突破性進(jìn)展。治療卵巢癌標(biāo)準(zhǔn)的化療方案是紫杉類聯(lián)合鉑類，部分患者對紫杉類及鉑類藥物不敏感，效果不佳，如果卵巢癌患者對紫杉類、鉑類藥物敏感性好，有利于提高化療有效率和延長患者生存期使之受益。因此探尋對鉑類和紫杉類化療敏感性的預(yù)測因子對指導(dǎo)臨床合理用藥非常重要。 TUBB3（class III beta-tubulin，β-微管蛋白III型)是細(xì)胞骨架的重要組成部分，在多種真核細(xì)胞和部分原核細(xì)胞中存在，能夠維持細(xì)胞形態(tài)結(jié)構(gòu)和參與細(xì)胞運(yùn)動，還在細(xì)胞的生長、分裂、凋亡和信息傳導(dǎo)中起著重要作用，而紫杉類藥物可特異性的與β微管蛋白III結(jié)合可阻滯其解聚，阻止有絲分裂的完成，從而引起細(xì)胞凋亡達(dá)到殺滅腫瘤的作用。有研究表明TUBB3與紫杉類等抗微管類化療藥物的耐藥密切相關(guān)，其高表達(dá)可以使紫杉類藥物降低對微管蛋白的解聚，，從而導(dǎo)致其耐藥。 核苷酸切除修復(fù)交叉互補(bǔ)基因1(excision repair cross-complementinggroup1，ERCC1)具有識別DNA損傷和鏈間切割的功能，是核苷酸剪切修復(fù)過程中最關(guān)鍵的一個內(nèi)切酶，其過表達(dá)可使腫瘤細(xì)胞停滯在G2/M期，能夠迅速修復(fù)損傷的DNA，引起對鉑類藥物耐藥。 P-糖蛋白（P-glycoprotein，P-gp）是ATP依賴性跨膜蛋白，不僅可能量依賴性地將藥物泵出細(xì)胞外，還能阻止化療藥物進(jìn)入到細(xì)胞內(nèi)從而減少細(xì)胞內(nèi)的藥物濃度；此外還可對細(xì)胞內(nèi)的藥物分布發(fā)生改變，把部分藥物都聚集在不能產(chǎn)生自身作用的細(xì)胞器中，使藥物達(dá)不到療效，從而導(dǎo)致耐藥。 目的: 通過檢測TUBB3、ERCC1和P-gp在卵巢癌組織及正常卵巢組織中的表達(dá)，分析三者分別與卵巢癌患者相關(guān)臨床病理因素之間的關(guān)系；探討TUBB3、ERCC1和P-gp在卵巢癌中表達(dá)的相關(guān)性，預(yù)測卵巢癌患者對藥物的敏感性及制定個體化治療方案提供依據(jù)。 方法： 收集手術(shù)切除并經(jīng)術(shù)后病理確診的卵巢癌組織50例和正常卵巢組織(雙附件無病理情況子宮肌瘤患者的手術(shù)切除卵巢為正常對照組)25例病理蠟塊，將篩選出的50例卵巢癌患者的完整病例資料進(jìn)行整理，術(shù)前均未接受化療、放療、生物免疫治療。用免疫組織化學(xué)法Envision兩步法檢測TUBB3、ERCC1、P-gp在卵巢癌組織中的表達(dá)，分析其與患者年齡、組織學(xué)類型、病理分級、臨床分期、腫瘤發(fā)生部位之間的關(guān)系；應(yīng)用SPSS17.0統(tǒng)計(jì)軟件處理數(shù)據(jù)，計(jì)數(shù)資料采用2檢驗(yàn)，相關(guān)性采用Spearman相關(guān)分析，均以α=0.05作為檢驗(yàn)標(biāo)準(zhǔn)，P＜0.05為差異有統(tǒng)計(jì)學(xué)意義。 結(jié)果： 免疫組織化學(xué)結(jié)果 1.TUBB3和ERCC1、P-gp在卵巢癌組織和正常卵巢組織中均有表達(dá)，TUBB3陽性表達(dá)定位于細(xì)胞漿，在卵巢癌組織表達(dá)陽性率為52.0%（26/50），正常卵巢組織中的陽性率表達(dá)為24.0%（6/25），顯著高于正常卵巢組織中表達(dá)，差異有統(tǒng)計(jì)學(xué)意義（2=7.038，P=0.008）；ERCC1陽性表達(dá)定位于細(xì)胞核，在卵巢癌組織中表達(dá)陽性率為70.0%（35/50），正常卵巢組織中的陽性率表達(dá)為32.0%（8/25），卵巢癌組顯著高于正常卵巢組，差異有統(tǒng)計(jì)學(xué)意義（2=9.420，P=0.002）；P-gp定位于細(xì)胞質(zhì)或細(xì)胞膜中，在卵巢癌組織表達(dá)陽性率為85.0%（42/50)，正常卵巢組織中的陽性率表達(dá)為40.0%（10/25)，卵巢癌組顯著高于正常卵巢組，差異有統(tǒng)計(jì)學(xué)意義（2=15.176，P=0.000）； 2.在蛋白質(zhì)水平上卵巢癌組織中TUBB3、ERCC1和P-gp的表達(dá)與病理分級及臨床分期有關(guān)（均P0.05)，其中腫瘤分期越晚三者的表達(dá)水平均越高，且在病理分級方面，亦是腫瘤分化程度越低表達(dá)水平越高，但三者與患者年齡、組織學(xué)類型、發(fā)生部位均無統(tǒng)計(jì)學(xué)差異（均P＞0.05）； 3.在卵巢癌組織中TUBB3和ERCC1的表達(dá)有相關(guān)性，且二者呈正相關(guān)，差異有統(tǒng)計(jì)學(xué)意義（P0.05）；TUBB3和P-gp在卵巢癌組織中的表達(dá)有相關(guān)性，且二者呈負(fù)相關(guān)，差異有統(tǒng)計(jì)學(xué)意義（P0.05）；卵巢癌組織中ERCC1的陽性表達(dá)率高于P-gp的表達(dá)，二者差異無統(tǒng)計(jì)學(xué)意義（P＞0.05），ERCC1表達(dá)與P-gp的表達(dá)無明顯相關(guān)性。 結(jié)論： TUBB3、ERCC1和P-gp在卵巢癌組織中有較高的陽性表達(dá)率，在正常卵巢組織中低表達(dá)，提示三者均可能參與了卵巢癌的發(fā)生、發(fā)展過程，且三者在卵巢癌組織中的表達(dá)均與腫瘤病理分級及臨床分期有關(guān)，病理分級越低、臨床分期越晚表達(dá)的陽性率越高，提示三者與卵巢癌的發(fā)生、發(fā)展及腫瘤耐藥有關(guān)；檢測TUBB3和ERCC1在卵巢癌組織中的表達(dá)呈正相關(guān)；TUBB3和P-gp在卵巢癌組織中的表達(dá)呈負(fù)相關(guān)；ERCC1和P-gp在卵巢癌組織中表達(dá)無相關(guān)性。由于化療耐藥機(jī)制的復(fù)雜性，提示同時檢測三者可能作為卵巢癌個體性化療方案的制定、對化療敏感性的重要指標(biāo)。
[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錛

本文編號：1799794