本文選題：卵巢癌 + 抗微管　； 參考：《承德醫(yī)學院》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，居婦科腫瘤的第二位[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、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。導致化療失敗并引起患者腫瘤復發(fā)、進展及死亡的主要原因是腫瘤細胞對化療藥物產生的多藥耐藥（multidrugresistance，MDR)。由多種基因、多因素和多步驟的復雜過程產生腫瘤耐藥，而P-糖蛋白（P-glycoprotein，P-gp）是多藥耐藥基因MDR1編碼產物，產生多藥耐藥性的主要原因是P-gp高表達，而P-gp耐藥機制是在臨床實踐中唯一得到證實的，解決此障礙，腫瘤化療效果將取得突破性進展。治療卵巢癌標準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測因子對指導臨床合理用藥非常重要。 TUBB3（class III beta-tubulin，β-微管蛋白III型)是細胞骨架的重要組成部分，在多種真核細胞和部分原核細胞中存在，能夠維持細胞形態(tài)結構和參與細胞運動，還在細胞的生長、分裂、凋亡和信息傳導中起著重要作用，而紫杉類藥物可特異性的與β微管蛋白III結合可阻滯其解聚，阻止有絲分裂的完成，從而引起細胞凋亡達到殺滅腫瘤的作用。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，其高表達可以使紫杉類藥物降低對微管蛋白的解聚，，從而導致其耐藥。 核苷酸切除修復交叉互補基因1(excision repair cross-complementinggroup1，ERCC1)具有識別DNA損傷和鏈間切割的功能，是核苷酸剪切修復過程中最關鍵的一個內切酶，其過表達可使腫瘤細胞停滯在G2/M期，能夠迅速修復損傷的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胞外，還能阻止化療藥物進入到細胞內從而減少細胞內的藥物濃度；此外還可對細胞內的藥物分布發(fā)生改變，把部分藥物都聚集在不能產生自身作用的細胞器中，使藥物達不到療效，從而導致耐藥。 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，分析三者分別與卵巢癌患者相關臨床病理因素之間的關系；探討TUBB3、ERCC1和P-gp在卵巢癌中表達的相關性，預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。 方法： 收集手術切除并經術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行整理，術前均未接受化療、放療、生物免疫治療。用免疫組織化學法Envision兩步法檢測TUBB3、ERCC1、P-gp在卵巢癌組織中的表達，分析其與患者年齡、組織學類型、病理分級、臨床分期、腫瘤發(fā)生部位之間的關系；應用SPSS17.0統(tǒng)計軟件處理數(shù)據，計數(shù)資料采用2檢驗，相關性采用Spearman相關分析，均以α=0.05作為檢驗標準，P＜0.05為差異有統(tǒng)計學意義。 結果： 免疫組織化學結果 1.TUBB3和ERCC1、P-gp在卵巢癌組織和正常卵巢組織中均有表達，TUBB3陽性表達定位于細胞漿，在卵巢癌組織表達陽性率為52.0%（26/50），正常卵巢組織中的陽性率表達為24.0%（6/25），顯著高于正常卵巢組織中表達，差異有統(tǒng)計學意義（2=7.038，P=0.008）；ERCC1陽性表達定位于細胞核，在卵巢癌組織中表達陽性率為70.0%（35/50），正常卵巢組織中的陽性率表達為32.0%（8/25），卵巢癌組顯著高于正常卵巢組，差異有統(tǒng)計學意義（2=9.420，P=0.002）；P-gp定位于細胞質或細胞膜中，在卵巢癌組織表達陽性率為85.0%（42/50)，正常卵巢組織中的陽性率表達為40.0%（10/25)，卵巢癌組顯著高于正常卵巢組，差異有統(tǒng)計學意義（2=15.176，P=0.000）； 2.在蛋白質水平上卵巢癌組織中TUBB3、ERCC1和P-gp的表達與病理分級及臨床分期有關（均P0.05)，其中腫瘤分期越晚三者的表達水平均越高，且在病理分級方面，亦是腫瘤分化程度越低表達水平越高，但三者與患者年齡、組織學類型、發(fā)生部位均無統(tǒng)計學差異（均P＞0.05）； 3.在卵巢癌組織中TUBB3和ERCC1的表達有相關性，且二者呈正相關，差異有統(tǒng)計學意義（P0.05）；TUBB3和P-gp在卵巢癌組織中的表達有相關性，且二者呈負相關，差異有統(tǒng)計學意義（P0.05）；卵巢癌組織中ERCC1的陽性表達率高于P-gp的表達，二者差異無統(tǒng)計學意義（P＞0.05），ERCC1表達與P-gp的表達無明顯相關性。 結論： TUBB3、ERCC1和P-gp在卵巢癌組織中有較高的陽性表達率，在正常卵巢組織中低表達，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均與腫瘤病理分級及臨床分期有關，病理分級越低、臨床分期越晚表達的陽性率越高，提示三者與卵巢癌的發(fā)生、發(fā)展及腫瘤耐藥有關；檢測TUBB3和ERCC1在卵巢癌組織中的表達呈正相關；TUBB3和P-gp在卵巢癌組織中的表達呈負相關；ERCC1和P-gp在卵巢癌組織中表達無相關性。由于化療耐藥機制的復雜性，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。
[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