本文選題：前列腺癌　切入點：FoxM1　出處：《中國人民解放軍醫(yī)學院》2015年博士論文

【摘要】：前列腺癌是威脅中老年男性生命的惡性腫瘤。近年在我國呈遞增趨勢。前列腺癌治療方案通常取決于是否發(fā)生周圍組織浸潤和轉移。因此對前列腺癌的早期診斷和轉移機制的研究具有重要意義。FoxM1參與腫瘤致病的多個環(huán)節(jié)；上皮-間質轉化是腫瘤轉移過程中的重要環(huán)節(jié)。剪切波彈性成像是鑒別腫瘤組織良惡性的重要方法。基于上述研究背景,本研究主要通過檢測FoxM1在前列腺癌組織中的表達,探討FoxM1參與前列腺癌EMT轉移機制及影響因素,并通過剪切波彈性成像初步探討人前列腺癌異種移植瘤彈性,并分析病理組織學基礎。方法：1FoxM1在前列腺癌組織及細胞表達的鑒定。檢測FoxM1蛋白及基因亞型在前列腺癌、良性前列腺增生組織及前列腺癌細胞系中的表達,分析FoxM1表達與前列腺癌病理Gleason評分的關系。檢測FoxM1 3個亞型FoxM1a、FoxM1b、 FoxM1c在前列腺癌組織和細胞系中的表達。2FoxM1參與前列腺癌細胞系EMT的體外實驗。建立前列腺癌細胞EMT模型,檢測FoxM1與EMT相關分子E-cadherin、vimentin、Slug表達變化,評估細胞運動遷移能力;二甲雙胍和低氧環(huán)境處理前列腺癌細胞,檢測FoxM1表達及EMT情況,評估細胞增殖、運動和遷移能力。3FoxM1參與前列腺癌轉移的動物實驗。構建攜載GFP的FoxM1 shRNA慢病毒載體,建立穩(wěn)定表達GFP和FoxM1 shRNA前列腺癌細胞株；建立裸鼠移植瘤模型,檢測移植瘤生長增殖及轉移情況。4.剪切波彈性成像評估移植瘤彈性.建立前列腺癌異種移植瘤模型,灰階超聲測量不同生長時間(6w、8w、10w)瘤體大小,剪切波彈性成像檢測瘤體彈性。分析瘤體組織內纖維成分,以及瘤體內膠原分型,檢測瘤體組織內α-SMA表達。建立FoxM1敲低移植瘤模型,生長8w時檢測上述指標.結果：1.FoxM1在前列腺癌組織和良性前列腺增生組織表達存在差異,在前列腺癌細胞系中均表達,在Gleason評分≥7的癌組織中表達明顯高于Gleason7的癌組織(p0.05)。FoxM1c亞型在前列腺癌組織和細胞中表達水平較高。2.TGF-p誘導前列腺癌細胞系EMT,E-cadherin下調,vimentin和Slug上調,細胞運動遷移能力增強,FoxM1敲低后,EMT過程逆轉。二甲雙胍處理細胞,內源性FoxM1表達下降,細胞增殖及運動遷移能力減弱；低氧環(huán)境下細胞內FoxM1表達增加,促進前列腺癌細胞EMT,細胞運動遷移能力增加。3.成功構建攜載GFP及FoxM1 shRNA的慢病毒載體,建立FoxM1敲低的前列腺癌移植模型。FoxM1敲低后成瘤能力弱,瘤體生長慢,轉移灶較對照組明顯減少。4.接種6w.8w.10w瘤體體積分別為832.58±14298mm3,1862.76±271.8mm3和2764.2±255.93mm3(p0.05)；瘤體楊氏模量分別為22.11±2.45KPa,44.89±3.02KPa和57.41±3.98KPa(p0.05)。在較硬瘤體中膠原纖維較多,膠原以Ⅰ型為主,且a-SMA表達較多。FoxM1敲低后瘤體較對照組生長緩慢,接種8w時瘤體大小分別為813.7686±111.1932mm3和1921.297±258.1513mm3(p0.05);楊氏模量分別為25.46±3.48KPa和46.94±5.32KPa(p0.05),在Fox M1敲低組膠原纖維成分較少,Ⅰ型膠原較少,且α^ A表達較少。結論FoxM1在前列腺癌組織中表達量增加,且與前列腺癌Gleason評分密切相關。FoxM1在前列腺癌EMT過程中具有重要作用,有望成為前列腺癌治療新的靶點。剪切波彈性成像能夠評價前列腺癌異種移植瘤彈性,對前列腺癌診斷具有重要的提示意義。
[Abstract]:Prostate cancer is a threat to life in elderly male malignant tumor in our country in recent years. By presenting the trend. Prostate cancer treatment protocol usually depends on whether the invasion and metastasis of the surrounding tissue. So the research aspects of early diagnosis and metastasis of prostate cancer is important parameter.FoxM1 and tumor disease; epithelial mesenchymal the transformation is an important link in the process of tumor metastasis. Shear wave elastography is an important method for identification of benign and malignant tumors. Based on the above research background, this research mainly through the detection of FoxM1 expression in prostate cancer tissues, to explore the mechanism and influence factors of the transfer of FoxM1 in prostate cancer EMT and human prostate cancer xenograft tumor of elastic the initial shear wave elastography, and analyze the pathological basis. Methods: 1FoxM1 expression in the identification of prostate cancer and detection of FoxM1 cells. The protein and gene expression in the subtype of prostate cancer, benign prostatic hyperplasia and prostate cancer cell lines, and analyze the relationship between FoxM1 expression and pathological Gleason score of prostate cancer. The detection of FoxM1 3 subtype FoxM1a, FoxM1b, FoxM1c in vitro in prostate cancer tissues and cell lines the expression of.2FoxM1 in prostate cancer cell lines EMT. The establishment of EMT prostate cancer cell model, detection of FoxM1 and EMT related molecules E-cadherin, vimentin, Slug expression, evaluation of cell movement ability; metformin and hypoxia treated prostate cancer cells, the expression of FoxM1 and EMT detection, assessment of cell proliferation, motility and migration of.3FoxM1 in animal experimental metastasis of prostate cancer. Construction of shRNA lentiviral vector carrying FoxM1 GFP, GFP FoxM1 shRNA and establish a stable expression in prostate cancer cell lines; nude mice transplantation, detection Tumor proliferation and metastasis of.4. shear wave elastography evaluation of transplanted tumor. The establishment of elastic prostate cancer xenograft model, ultrasound measurement of different growth time (6W, 8W, 10W) tumor size, shear wave elastography detection of tumors. Analysis of elastic fiber components of tumor tissue, and in vivo tumor type collagen the expression of alpha, -SMA detection of tumor tissue. FoxM1 knockdown xenograft model, the growth of 8W detected the target. Results: the expression of 1.FoxM1 in prostate cancer and benign prostatic hyperplasia tissue differences were expressed in prostate cancer cells, the Gleason expression was significantly higher than that of Gleason7 score more than 7 of the cancer tissues in (P0.05).FoxM1c subtype in prostate cancer cells and the expression of prostate cancer cell line EMT induced by high levels of.2.TGF-p vimentin and downregulation of E-cadherin, upregulation of Slug, cell transport capacity increase 844000 shift Strong, FoxM1 knockdown, EMT process was reversed. Metformin treated cells, the expression of endogenous FoxM1 decreased, decreased the proliferation and motility of cell migration; hypoxia cells increase the expression of FoxM1, promote prostate cancer cell EMT, cell movement and migration increased.3. constructed successfully lentiviral vector carrying GFP and FoxM1 shRNA, set up FoxM1 on.FoxM1 prostate cancer xenograft model of low knockdown tumor formation ability is weak, slow tumor growth, metastasis significantly reduced compared with the control group.4. were inoculated with 6w.8w.10w tumor volume were 832.58 + 14298mm31862.76 + 271.8mm3 and 2764.2 + 255.93mm3 (P0.05); tumor modulus were 22.11 + 2.45KPa, 44.89 + 3.02KPa and 57.41 + 3.98KPa (P0.05). The harder the tumor in the collagen fibers, collagen type I, and the expression of a-SMA is more.FoxM1 knockdown tumor than in the control group grew slowly, when inoculated with 8W tumor size respectively. 813.7686 + 111.1932mm3 and 1921.297 + 258.1513mm3 (P0.05); the young's modulus were 25.46 + 3.48KPa and 46.94 + 5.32KPa (P0.05, Fox) in M1 knockdown group collagen type I collagen composition is less and less, alpha ^ A expression less. Conclusion FoxM1 in prostate cancer was increased, and the score with prostate cancer is closely related to Gleason.FoxM1 plays an important role in prostate cancer EMT process, is expected to become a new target for treatment of prostate cancer. The shear wave elastography can evaluate the prostate cancer xenograft tumor elasticity, has important implications for diagnosis of prostate cancer.

【學位授予單位】：中國人民解放軍醫(yī)學院
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R737.25

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