上皮性卵巢癌的复发耐药与肿瘤组织中MicroRNA-145和OCT4表达水平的相关性研究

发布时间：2018-01-31 02:30

  本文关键词： 上皮性卵巢癌 耐药 复发 OCT4 miR-145　出处：《河北医科大学》2014年硕士论文　论文类型：学位论文

【摘要】：目的：卵巢癌(ovary cancer，，OC)是最常见的女性生殖道恶性肿瘤之一，占所有女性癌症的第六位。上皮性卵巢癌(epithelial ovary cancer EOC)是最多见的卵巢癌，约占原发卵巢肿瘤的50%-70%。在所有妇科肿瘤中病死率最高，每年约导致125,000患者死亡。上皮性卵巢癌的死亡率高主要是因为其起病迅速，早期缺乏特异性的症状和体征，超过70%的卵巢癌患者初诊时已属晚期，失去了最佳治疗时机。如早期发现卵巢癌肿瘤仍局限在卵巢内，那么患者的5年生存率大于90%。晚期病变造成的癌性粘连、远处转移使手术不能彻底清除病灶。卵巢癌目前首选的治疗方案为减瘤术加化疗，铂类和紫杉醇联合化疗为一线方案。尽管诊断和化疗技术在不断发展，但至今晚期患者的5年生存率仍仅为30%，且大多数患者会复发并产生耐药。 肿瘤干细胞学说是近年来随着肿瘤研究的深入学者们所热衷的一种学说。干细胞是指那种未分化的具有自我更新、无限增殖能力和多向分化潜能的一类细胞。信号分子Octamer4（OCT4）是转录因子POU家族的成员之一，在肿瘤干细胞、胚胎干细胞以及成人干细胞中均呈高表达。OCT4的过表达可维持胚胎干细胞的自我更新、无限增殖和去分化能力。MicroRNAs是一类小RNA分子，它能以不完全互补方式与靶mRNA的3非翻译端的特定区域相互作用，导致mRNA的切割裂解或蛋白翻译抑制，进而影响靶基因的表达和作用。前期研究中已发现OCT4的表达与子宫内膜癌患者肿瘤分化级别呈负相关，而miR-145与之相反，与肿瘤的分级呈正相关。由此我们推测在上皮性卵巢癌中miR-145是否也可作用于OCT4，通过抑制其表达，进而对肿瘤的复发和耐药起到积极的影响作用。本研究将观察卵巢癌患者肿瘤组织中miR-145和OCT4的不同表达，并分析其与肿瘤复发和耐药的关系，以期能找到一种敏感有效的检测方法，为上皮性卵巢癌患者预后的分析和疗效的判定提供有利的依据，解决临床工作中现存的难题。 方法：选取6例正常卵巢组织和29例上皮性卵巢癌患者的手术标本，病例来自河北医科大学第二医院、河北医科大学第四医院及第三医院2011-2013年上皮性卵巢癌患者手术标本，并且由河北医科大学第二医院病理科确认核实为上皮性卵巢癌。依据实验目的分为耐药组和不耐药组及对照组，采用免疫组化方法检测其OCT4的表达水平及采用Real-TimePCR方法检测miR-145的表达水平。探讨上皮性卵巢癌的复发耐药与肿瘤组织中miR-145与OCT4表达水平的相关性。 结果： 1OCT4在正常卵巢组织及上皮性卵巢癌中的表达 免疫组化结果显示，OCT4在正常卵巢组织、上皮性卵巢癌不耐药组及耐药组的阳性表达率分别为20.00%、36.37%、82.35%。 1.1OCT4在正常卵巢组织与不耐药组的表达水平无显著差异（Fisher'sExact Test P=0.600.05）； 1.2OCT4在正常组表达水平低于耐药组，两者有显著差异（Fisher's ExactTest P=0.0090.05）； 1.3OCT4在不耐药组的表达水平低于耐药组，两组存在显著差异（Fisher'sExact Test P=0.020.05）。 2MicroRNA-145在正常卵巢及上皮性卵巢癌组织中的表达Real-Time PCR结果显示，MiR-145在正常卵巢组织、上皮性卵巢癌不耐药组及耐药组中的表达水平逐渐升高，分别为1.0483±0.8989、0.8236±0.6423、0.5224±0.7862。并且在三组中的表达均存在显著差异。 2.1MiR-145在正常卵巢组织的表达水平高于不耐药组，两者的表达存在显著差异（t=5.998P=0.000.05）； 2.2MiR-145在正常卵巢组织的表达水平高于耐药组，两者的表达存在显著差异（t=13.596P=0.000.05）； 2.3MiR-145在上皮性卵巢癌不耐药组的表达水平高于耐药组，两者的表达存在显著差异（t=10.605P=0.000.05）。 结论：本研究采用免疫组化和实时定量PCR方法技术检测了在正常卵巢组织及上皮性卵巢癌中OCT4和miR-145的表达变化，结果显示，OCT4在正常卵巢组织及上皮性卵巢癌组织中均有表达，并且在癌组织中的表达水平升高。OCT4在耐药组中的表达明显高于不耐药组，两者存在显著差异。miR-145在正常卵巢组织及上皮性卵巢癌组织中也均有表达，但其与OCT4相反，miR-145在癌组织中表达水平下降。miR-145在耐药组的表达水平低于不耐药组，两者存在显著差异。但是在上皮性卵巢癌中OCT4与miR-145之间是否存在内在关联，OCT4及miR-145能否作为一种敏感有效的检测上皮性卵巢癌复发耐药的方法，为上皮性卵巢癌患者预后的分析和疗效的判定提供有利的依据，还待进一步研究。
[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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