本文關(guān)鍵詞： 上皮性卵巢癌 耐藥 復(fù)發(fā) OCT4 miR-145　出處：《河北醫(yī)科大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：目的：卵巢癌(ovary cancer，，OC)是最常見的女性生殖道惡性腫瘤之一，占所有女性癌癥的第六位。上皮性卵巢癌(epithelial ovary cancer EOC)是最多見的卵巢癌，約占原發(fā)卵巢腫瘤的50%-70%。在所有婦科腫瘤中病死率最高，每年約導(dǎo)致125,000患者死亡。上皮性卵巢癌的死亡率高主要是因為其起病迅速，早期缺乏特異性的癥狀和體征，超過70%的卵巢癌患者初診時已屬晚期，失去了最佳治療時機。如早期發(fā)現(xiàn)卵巢癌腫瘤仍局限在卵巢內(nèi)，那么患者的5年生存率大于90%。晚期病變造成的癌性粘連、遠處轉(zhuǎn)移使手術(shù)不能徹底清除病灶。卵巢癌目前首選的治療方案為減瘤術(shù)加化療，鉑類和紫杉醇聯(lián)合化療為一線方案。盡管診斷和化療技術(shù)在不斷發(fā)展，但至今晚期患者的5年生存率仍僅為30%，且大多數(shù)患者會復(fù)發(fā)并產(chǎn)生耐藥。 腫瘤干細胞學(xué)說是近年來隨著腫瘤研究的深入學(xué)者們所熱衷的一種學(xué)說。干細胞是指那種未分化的具有自我更新、無限增殖能力和多向分化潛能的一類細胞。信號分子Octamer4（OCT4）是轉(zhuǎn)錄因子POU家族的成員之一，在腫瘤干細胞、胚胎干細胞以及成人干細胞中均呈高表達。OCT4的過表達可維持胚胎干細胞的自我更新、無限增殖和去分化能力。MicroRNAs是一類小RNA分子，它能以不完全互補方式與靶mRNA的3非翻譯端的特定區(qū)域相互作用，導(dǎo)致mRNA的切割裂解或蛋白翻譯抑制，進而影響靶基因的表達和作用。前期研究中已發(fā)現(xiàn)OCT4的表達與子宮內(nèi)膜癌患者腫瘤分化級別呈負相關(guān)，而miR-145與之相反，與腫瘤的分級呈正相關(guān)。由此我們推測在上皮性卵巢癌中miR-145是否也可作用于OCT4，通過抑制其表達，進而對腫瘤的復(fù)發(fā)和耐藥起到積極的影響作用。本研究將觀察卵巢癌患者腫瘤組織中miR-145和OCT4的不同表達，并分析其與腫瘤復(fù)發(fā)和耐藥的關(guān)系，以期能找到一種敏感有效的檢測方法，為上皮性卵巢癌患者預(yù)后的分析和療效的判定提供有利的依據(jù)，解決臨床工作中現(xiàn)存的難題。 方法：選取6例正常卵巢組織和29例上皮性卵巢癌患者的手術(shù)標本，病例來自河北醫(yī)科大學(xué)第二醫(yī)院、河北醫(yī)科大學(xué)第四醫(yī)院及第三醫(yī)院2011-2013年上皮性卵巢癌患者手術(shù)標本，并且由河北醫(yī)科大學(xué)第二醫(yī)院病理科確認核實為上皮性卵巢癌。依據(jù)實驗?zāi)康姆譃槟退幗M和不耐藥組及對照組，采用免疫組化方法檢測其OCT4的表達水平及采用Real-TimePCR方法檢測miR-145的表達水平。探討上皮性卵巢癌的復(fù)發(fā)耐藥與腫瘤組織中miR-145與OCT4表達水平的相關(guān)性。 結(jié)果： 1OCT4在正常卵巢組織及上皮性卵巢癌中的表達 免疫組化結(jié)果顯示，OCT4在正常卵巢組織、上皮性卵巢癌不耐藥組及耐藥組的陽性表達率分別為20.00%、36.37%、82.35%。 1.1OCT4在正常卵巢組織與不耐藥組的表達水平無顯著差異（Fisher'sExact Test P=0.600.05）； 1.2OCT4在正常組表達水平低于耐藥組，兩者有顯著差異（Fisher's ExactTest P=0.0090.05）； 1.3OCT4在不耐藥組的表達水平低于耐藥組，兩組存在顯著差異（Fisher'sExact Test P=0.020.05）。 2MicroRNA-145在正常卵巢及上皮性卵巢癌組織中的表達Real-Time PCR結(jié)果顯示，MiR-145在正常卵巢組織、上皮性卵巢癌不耐藥組及耐藥組中的表達水平逐漸升高，分別為1.0483±0.8989、0.8236±0.6423、0.5224±0.7862。并且在三組中的表達均存在顯著差異。 2.1MiR-145在正常卵巢組織的表達水平高于不耐藥組，兩者的表達存在顯著差異（t=5.998P=0.000.05）； 2.2MiR-145在正常卵巢組織的表達水平高于耐藥組，兩者的表達存在顯著差異（t=13.596P=0.000.05）； 2.3MiR-145在上皮性卵巢癌不耐藥組的表達水平高于耐藥組，兩者的表達存在顯著差異（t=10.605P=0.000.05）。 結(jié)論：本研究采用免疫組化和實時定量PCR方法技術(shù)檢測了在正常卵巢組織及上皮性卵巢癌中OCT4和miR-145的表達變化，結(jié)果顯示，OCT4在正常卵巢組織及上皮性卵巢癌組織中均有表達，并且在癌組織中的表達水平升高。OCT4在耐藥組中的表達明顯高于不耐藥組，兩者存在顯著差異。miR-145在正常卵巢組織及上皮性卵巢癌組織中也均有表達，但其與OCT4相反，miR-145在癌組織中表達水平下降。miR-145在耐藥組的表達水平低于不耐藥組，兩者存在顯著差異。但是在上皮性卵巢癌中OCT4與miR-145之間是否存在內(nèi)在關(guān)聯(lián)，OCT4及miR-145能否作為一種敏感有效的檢測上皮性卵巢癌復(fù)發(fā)耐藥的方法，為上皮性卵巢癌患者預(yù)后的分析和療效的判定提供有利的依據(jù)，還待進一步研究。
[Abstract]:Objective: ovarian cancer (ovary, cancer, OC) is one of the most common malignant tumor of the female genital tract, accounting for sixth of all female cancer. Epithelial ovarian cancer (epithelial ovary cancer EOC) is the most common ovarian cancer, accounting for 50%-70%. of primary ovarian tumors in all gynecological cancer mortality each year about 125000 deaths caused. Epithelial ovarian cancer mortality is mainly because of its rapid onset, the lack of specific symptoms and signs of early ovarian cancer, more than 70% of the patients with late stage and lost the best treatment time. Such as the early detection of ovarian cancer is still confined to the ovary, then in 5 year survival rate of more than 90%. of advanced lesions caused by cancer adhesion, metastasis to surgery can not completely remove the lesion. Ovarian cancer is the preferred treatment for cytoreductive surgery plus chemotherapy, cisplatin and paclitaxel combined with chemotherapy as first-line Despite the continuous development of diagnostic and chemotherapeutic techniques, the 5 year survival rate for advanced patients is still only 30%, and most patients will relapse and produce drug resistance.
The cancer stem cell theory is a theory in recent years, with the in-depth research scholars are keen on tumor. Stem cell is a kind of undifferentiated self-renewal, a cell proliferate and differentiate. The signaling molecule Octamer4 (OCT4) is a member of the POU transcription factor family, in tumor stem cells, embryonic stem cells and adult stem cells showed high expression expression can maintain stem cell self-renewal and differentiation ability of.OCT4,.MicroRNAs proliferation is a kind of small RNA molecules, it can not completely complementary interaction between 3 translation methods and non target mRNA end of a particular area, leading to mRNA cut cleavage or translation inhibition protein, thereby affecting the expression and function of target genes. The expression of OCT4 was negatively correlated with endometrial cancer differentiation level has been found in previous research, and miR-145 in contrast with Grade was positively related to the tumor. Thus we speculate that in epithelial ovarian cancer whether miR-145 has effects on OCT4 by inhibiting its expression, and resistance to tumor recurrence and played a positive role. This study will observe the different expression of miR-145 and OCT4 in ovarian cancer tumor tissue, and analyze its relationship with tumor recurrence and drug resistance, in order to find a sensitive and effective method for the detection, analysis and prognosis of patients with epithelial ovarian cancer determined to provide the advantageous basis, to solve the existing problems in the clinical work.
Methods: surgical specimens from 6 cases of normal ovarian tissues and 29 cases of epithelial ovarian cancer patients, second cases from the Hebei Medical University hospital, the fourth hospital of Hebei Medical University and three hospital 2011-2013 years of operation in patients with epithelial ovarian cancer specimens, and by the second hospital of Hebei Medical University, Department of Pathology confirmation for epithelial ovarian cancer. According to the experimental purpose into the resistance group and the resistance group and the control group, the expression level of expression was detected by immunohistochemical method of OCT4 and Real-TimePCR was detected by miR-145 method. To investigate the expression of miR-145 and OCT4, the relationship between the level of drug resistance and tumor recurrence of epithelial ovarian cancer.
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本文編號：1477934