本文選題：食管鱗狀細胞癌 + miR-613��； 參考：《山東大學》2017年博士論文

【摘要】：目的:食管癌是最常見的消化道惡性腫瘤之一,在未來10年發(fā)生率會不斷增高。患者的預后較差,五年生存率僅為150%-250%左右。對于食管癌標志物的探索是近幾年迅速發(fā)展的研究領域,對于食管癌的早期診斷以及預后評估有重要作用。近期大量研究表明,血小板計數(shù)、腫瘤長度以及營養(yǎng)狀態(tài)等指標與食管癌患者的預后密切相關。食管癌患者的早期診斷對于改善患者預后意義重大。miRNA的表達水平高低可以作為腫瘤的診斷和預后指標,用于評價腫瘤發(fā)生、進展以及治療效果。例如,血清miR-25、miR-223和miR-375可以作為食管鱗癌的診斷指標。血清miR-24和miR-200c同樣可以作為評價患者化療和同步放化療療效的無創(chuàng)性指標。miR-613在不同的腫瘤中發(fā)揮不同的作用,在乳頭狀甲狀腺癌中低表達,在胃癌中卻為高表達�？梢园邢蛘{節(jié)FNA基因以及Wnt通路。然而,miR-613在食管癌中的表達水平及其作用機制尚不明確。本文目的:探討miR-613在食管癌腫瘤組織以及血清中的表達水平,并進一步探討了其臨床診斷和預后評價價值。資料和方法:我們納入了齊魯醫(yī)院2014-10到2015-03之間胸外科75名擬接受手術治療的食管癌患者的術前血清樣本,同時收集了年齡及性別與之配對的正常人群的血清樣本作為對照組。同時,我們收集了其中60位患者的食管癌組織及其周圍正常組織(15例患者未行手術治療,因拒絕手術或身體狀態(tài)不適宜手術),術后30min內收集好腫瘤組織和癌旁組織,用液氮轉移至-80度冰箱中保存。我們還收集了 2009年齊魯醫(yī)院病理科的109名食管鱗癌患者的福爾馬林固定石蠟包埋的組織標本(FFPE)。所有患者均經(jīng)手術或食管鏡活檢診斷為食管鱗癌�；颊呔葱行g前抗腫瘤治療。我們統(tǒng)計分析了患者的年齡、性別、吸煙及飲酒情況、腫瘤長度、位置、浸潤深度(T分期)、淋巴結轉移程度(N分期)、遠處轉移(M分期)以及分化程度總RNA提取及qRT-PCR檢測RT反應體系總共25ul,qPCR體系為20ul,RNU6B和miR-16分別作為組織和血清中的內參。組織和血清中miR-613的相對表達量采用2-△ △Ct計算,FFPE中的表達量采用2-△ Ct計算。實驗結果:1、食管鱗癌患者組織中miR-613的表達情況我們采用qRT-PCR方法分析腫瘤組織和癌旁正常組織中miR-613表達量。與正常組織相比,腫瘤組織miR-613的表達呈下調趨勢(0.34±0.56vs.1.08±0.07,P0.001)。同時分析miR-613的表達水平與患者臨床特征之間的關系,我們發(fā)現(xiàn)miR-613的表達水平與患者T分期呈負相關(P=0.008)。2、血清miR-613的表達水平及其診斷價值我們首先假設組織miR-613的表達水平可能會影響血清中的表達情況。實驗結果顯示患者血清miR-613也為低表達趨勢(0.89±0.73 vs.1.71 士 1.03,P0.001)。血清miR-613的表達水平與患者N分期呈明顯負相關(P=0.038),而與其他指標沒有明顯相關性。我們分析了患者食管癌組織miR-613與血清miR-613表達的相關性,Pearson相關系數(shù)為0.812(P0.001)。我們分析了血清miR-613的診斷價值,曲線下面積(AUC)為0.767±0.040。Yuden指數(shù),即cut-off值為0.875,R0C曲線的敏感性和特異性值分別為81.3%and 62.7%。對早期患者數(shù)據(jù)的進一步分析發(fā)現(xiàn),AUC值為0.728±0.052(P0.001)。3、miR-613在食管鱗癌患者預后的預測價值我們收集了 109名食管癌患者的FFPE標本,miR-613的平均表達水平為0.0016(cut-off值)。miR-613的表達水平與患者臨床特征之間沒有明顯相關性�；颊叩钠骄鏁r間為39個月(分布區(qū)間為6-81月)。截至末次隨訪,35名患者(32.11%)仍健在,而74名患者(67.89%)已去世。K-M曲線分析提示miR-613低表達組患者的五年總生存時間(0S)及無進展生存時間(PFS)明顯較短(P= 0.018和P=0.035,respectively,)。進一步的多因素分析提示miR-613是患者 OS(HR(95%CI)0.591(0.336-0.954),P=0.031)和 PFS(HR(95%CI)0.656(0.485-0.888),P = 0.006,)良好的預后指標。結論:(1)與正常組織相比,腫瘤組織miR-613的表達呈下調趨勢;(2)腫瘤組織中miR-613的表達水平與患者T分期呈負相關;(3)患者食管癌組織miR-613與血清miR-613表達的一定的正相關性,血清miR-613的表達水平與患者N分期呈明顯負相關,并且具有一定的診斷價值;(4)miR-613低表達提示患者預后較差。
[Abstract]:Objective: esophageal cancer is one of the most common digestive tract malignant tumors. The incidence of esophageal cancer in the next 10 years is increasing. The prognosis of the patients is poor and the five year survival rate is only about 150%-250%. The exploration of the esophageal cancer markers is a rapid development in recent years. It has an important role in the early diagnosis and prognosis evaluation of esophageal cancer. A large number of studies have shown that the platelet count, tumor length, and nutritional status are closely related to the prognosis of patients with esophageal cancer. Early diagnosis of patients with esophageal cancer can be used as a diagnostic and prognostic marker for the improvement of the prognosis of patients with.MiRNA, which is used to evaluate the occurrence, progress and therapeutic effect of cancer. For example, serum miR-25, miR-223, and miR-375 can be used as diagnostic indicators for squamous cell carcinoma of the esophagus. Serum miR-24 and miR-200c can also be used as a noninvasive index to evaluate the efficacy of chemotherapy and concurrent chemoradiotherapy..miR-613 plays a different role in different tumors, low expression in papillary thyroid carcinoma and high expression in gastric cancer. It can be targeted to regulate FNA gene and Wnt pathway. However, the expression level and mechanism of miR-613 in esophageal cancer are not clear. Objective: To explore the expression level of miR-613 in the tumor tissues and serum of esophageal cancer, and to further explore the value of its clinical diagnosis and prognosis evaluation. The preoperative serum samples of 75 patients with surgical treatment of esophageal cancer were collected from 2014-10 to 2015-03 in the hospital, and serum samples of age and sex matched normal people were collected as the control group. At the same time, we collected 60 of the patients' esophageal cancer tissues and its surrounding normal tissues (15 patients were not treated by surgery. " The tumor tissue and paracancerous tissue were collected and transferred to the -80 degree refrigerator at 30min after the operation. We also collected the formalin fixed paraffin embedded tissue specimens (FFPE) of 109 patients with esophageal squamous cell carcinoma in Qilu Hospital in 2009. All patients were operated by surgery or Esophageal squamous cell carcinoma was diagnosed as squamous cell carcinoma of the esophagus. All patients were not treated with preoperative antitumor treatment. We statistically analyzed age, sex, smoking and drinking, tumor length, location, depth of infiltration (T staging), lymph node metastasis (N staging), distant metastasis (M phase), total RNA extraction and qRT-PCR detection of RT reaction system. A total of 25ul, qPCR system was 20ul, RNU6B and miR-16 were used as internal parameters in tissue and serum respectively. The relative expression of miR-613 in tissue and serum was calculated by 2- Delta Ct, and the expression in FFPE was calculated by 2- Delta Ct. Experimental results: 1, the expression of miR-613 in tissues of patients with esophageal squamous cell carcinoma was analyzed by the method of analysis of tumor tissue and Compared with normal tissue, the expression of miR-613 in the tumor tissue was down downward (0.34 + 0.56vs.1.08 + 0.07, P0.001). Meanwhile, the relationship between the expression level of miR-613 and the clinical features of the patients was also analyzed. We found that the expression level of miR-613 was negatively correlated with the T stage of the patients (P=0.008).2 and serum miR-613. We first hypothesized that the expression level of the tissue miR-613 might affect the expression in the serum. The experimental results showed that the serum miR-613 was also a low expression trend (0.89 + 0.73 vs.1.71 1.03, P0.001). The expression level of serum miR-613 was negatively correlated with the patients' N staging (P=0.038), but with the other fingers. The correlation between miR-613 and serum miR-613 expression was analyzed. The Pearson correlation coefficient was 0.812 (P0.001). We analyzed the diagnostic value of serum miR-613. The area under the curve (AUC) was 0.767 + 0.040.Yuden index, that is, cut-off value was 0.875, and the sensitivity and specificity of R0C curve were 8, respectively. 1.3%and 62.7%.'s further analysis of early patient data found that the AUC value was 0.728 + 0.052 (P0.001).3. The predictive value of miR-613 in the prognosis of esophageal squamous cell carcinoma we collected the FFPE specimens of 109 esophageal cancer patients. The average expression level of miR-613 was 0.0016 (cut-off).MiR-613 expression and the patient's clinical characteristics were not between them. The average survival time of the patients was 39 months (6-81 months in the distribution interval). 35 patients (32.11%) were still alive at the end of the last follow-up, and 74 patients (67.89%) had passed the.K-M curve analysis. The total survival time (0S) and the progression free survival time (PFS) in the miR-613 low expression group were significantly shorter (P= 0.018 and P=0.035, respe, respe). Ctively. Further multivariate analysis suggested that miR-613 was a good prognostic indicator for patients with OS (HR (95%CI) 0.591 (0.336-0.954) 0.591 (0.336-0.954), P=0.031) and PFS (HR (95%CI) 0.656 (0.485-0.888), P = 0.006). Conclusion: (1) the expression of tumor tissue was down downward trend compared with normal tissue; (2) the expression level of the tumor tissue was compared with the patient. There was a negative correlation. (3) there was a positive correlation between the miR-613 and the expression of serum miR-613 in the patients with esophageal cancer. The expression level of serum miR-613 was negatively correlated with the N staging of the patients, and was of certain diagnostic value; (4) the low expression of miR-613 suggested that the prognosis of the patients was poor.
【學位授予單位】：山東大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R735.1

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