發(fā)布時(shí)間：2018-03-20 12:00

  本文選題：卵巢癌　切入點(diǎn)：YKL-40　出處：《山東大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：卵巢癌是婦科三大常見惡性腫瘤之一,上皮性卵巢癌(EOC)為主要病理類型(85%以上),死亡率高居女性腫瘤相關(guān)性死亡之首。上皮性卵巢癌惡性程度高,早期癥狀隱匿,且極易發(fā)生侵襲轉(zhuǎn)移,致使70%的患者在確診時(shí)即已出現(xiàn)盆腹腔器官的侵襲播散和(或)遠(yuǎn)處臟器的轉(zhuǎn)移。目前,最大程度的外科減瘤術(shù)和術(shù)后鉑類、紫杉醇的聯(lián)合化療是上皮性卵巢癌的主要治療手段,并可使大部分的患者獲得緩解。但仍有75%-80%的晚期患者在治療后復(fù)發(fā),并在之后進(jìn)行的重復(fù)循環(huán)的化療過(guò)程中發(fā)生獲得性耐藥,出現(xiàn)對(duì)鉑類等一線化療方案藥物敏感性的降低。上皮性卵巢癌的高侵襲轉(zhuǎn)移特性以及耐藥的出現(xiàn),是阻礙患者預(yù)后、導(dǎo)致患者高死亡率的重要原因,嚴(yán)重威脅了女性的健康。因此,探討并闡明影響卵巢癌轉(zhuǎn)移和化學(xué)耐藥的參與分子和機(jī)制具有重要意義。YKL-40,又被稱作殼質(zhì)酶3樣1(CHI3L1),是一種分泌型糖蛋白,在乳腺癌、肺癌、腦膠質(zhì)瘤等多種惡性腫瘤中高表達(dá)。研究表明,YKL-40可通過(guò)多種機(jī)制參與惡性腦膠質(zhì)瘤、子宮內(nèi)膜癌等腫瘤細(xì)胞的侵襲轉(zhuǎn)移過(guò)程。另有研究證實(shí),YKL-40分子可通過(guò)AKT/ERK通路介導(dǎo)耐替莫唑胺(TMZ)的腦膠質(zhì)瘤細(xì)胞株(TMZ-R U87)對(duì)替莫唑胺的耐藥。然而,YKL-40是否可影響EOC細(xì)胞的遷移能力及對(duì)鉑類藥物的敏感性,還尚不明確。本研究選用經(jīng)典的EOC細(xì)胞系SKOV-3細(xì)胞作為研究對(duì)象,共分三個(gè)部分,分別從體外驗(yàn)證YKL-40分子對(duì)上皮性卵巢癌細(xì)胞的遷移能力以及鉑類藥物敏感性的影響,并探討相關(guān)調(diào)控因子。第一部分 YKL-40在卵巢癌SKOV-3細(xì)胞的表達(dá)[目的]檢測(cè)EOC細(xì)胞SKOV-3中YKL-40分子的表達(dá)。[方法]選用膠質(zhì)母細(xì)胞瘤U87細(xì)胞作為陽(yáng)性對(duì)照,采用RT-PCR、ELISA、Western Blot試驗(yàn),分別從mRNA和蛋白水平檢測(cè)SKOV-3細(xì)胞中YKL-40的表達(dá)水平。[結(jié)果]在陽(yáng)性對(duì)照U87細(xì)胞中,RT-PCR及ELISA可檢測(cè)到Y(jié)KL-40的顯著表達(dá),其瓊脂糖凝膠電泳可見YKL-40 mRNA擴(kuò)增產(chǎn)物,細(xì)胞上清分泌水平的表達(dá)量為(18.41±1.69)ng/mL;而在SKOV-3細(xì)胞,無(wú)論mRNA水平還是分泌蛋白水平,均未檢測(cè)到Y(jié)KL-40的表達(dá)。[結(jié)論]YKL-40在SKOV-3細(xì)胞無(wú)明顯表達(dá)。第二部分 YKL-40對(duì)卵巢癌SKOV-3細(xì)胞體外遷移能力的影響[目的]探討YKL-40對(duì)EOC細(xì)胞SKOV-3體外遷移能力的影響及相關(guān)分子機(jī)制。[方法]根據(jù)第一部分檢測(cè)結(jié)果,構(gòu)建YKL-40過(guò)表達(dá)慢病毒,采用慢病毒感染的方法構(gòu)造過(guò)表達(dá)YKL-40的SKOV-3細(xì)胞株LV-SKOV-3細(xì)胞,和空載體陰性對(duì)照細(xì)胞株 NC-SKOV-3,qRT-PCR、ELISA、Western Blot 驗(yàn)證 YKL-40過(guò)表達(dá)情況;Transwell試驗(yàn)檢測(cè)YKL-40過(guò)表達(dá)對(duì)SKOV-3遷移能力的影響;特異性抑制劑阻滯過(guò)表達(dá)細(xì)胞中p38 MAPK通路,檢測(cè)細(xì)胞遷移能力的改變。[結(jié)果]1.成功構(gòu)建YKL-40過(guò)表達(dá)細(xì)胞株LV-SKOV-3及空載體陰性對(duì)照細(xì)胞株NC-SKOV-3。qRT-PCR、ELISA、Western Blot 檢測(cè)到 LV-SKOV-3 細(xì)胞 YKL-40表達(dá)顯著增強(qiáng),其mRNA的相對(duì)表達(dá)量為NC-SKOV-3細(xì)胞的9.89倍,蛋白分泌量達(dá)(32.35±1.38)ng/ml,為 NC-SKOV-3 細(xì)胞的 17.43 倍。2.LV-SKOV-3細(xì)胞的遷移數(shù)量平均為(255.75士 12.75)個(gè)/視野,NC-SKOV-3細(xì)胞為(119.25±13.25)個(gè)/視野。LV-SKOV-3細(xì)胞的遷移數(shù)量上調(diào)為空載體陰性對(duì)照細(xì)胞的1.14倍。3.抑制p38 MAPK通路,可部分下調(diào)LV-SKOV-3的遷移能力。Transwell試驗(yàn)結(jié)果示,抑制劑組LV-SKOV-3細(xì)胞的遷移數(shù)量較DMSO對(duì)照組減少,為對(duì)照組的 63.30%。[結(jié)論]YKL-40分子可顯著增強(qiáng)上皮性卵巢癌SKOV-3細(xì)胞的遷移能力,且這一作用可能是通過(guò)p38 MAPK通路介導(dǎo)的。第三部分 YKL-40對(duì)卵巢癌SKOV-3細(xì)胞化療藥物敏感性的影響[目的]探討YKL-40對(duì)卵巢癌SKOV-3細(xì)胞鉑類藥物敏感性的影響及相關(guān)分子機(jī)制。[方法]Western Blot試驗(yàn)檢測(cè)LV-SKOV-3細(xì)胞中NF-κB分子的表達(dá);NF-κB 特異性抑制劑、ELISA、Western Blot 檢測(cè) NF-κB 對(duì) SKOV-3 細(xì)胞 YKL-40蛋白表達(dá)的調(diào)控;分別采用不同濃度(1μg/ml、2.5μg/ml、5μg/ml、1.0μg/ml)的順鉑(DDP)處理YKL-40過(guò)表達(dá)LV-SKOV-3細(xì)胞和空載體陰性對(duì)照NC-SKOV-3細(xì)胞48h,CCK-8試驗(yàn)檢測(cè)細(xì)胞的抑制率;抑制劑Bay11-7082特異性抑制LV-SKOV-3細(xì)胞中的NF-κB,CCK-8試驗(yàn)再次檢測(cè)細(xì)胞LV-SKOV-3對(duì)DDP敏感性的變化。[結(jié)果]1.Western Blot結(jié)果顯示,LV-SKOV-3細(xì)胞中NF-κB蛋白表達(dá)水平較陰性對(duì)照NC-SKOV-3細(xì)胞增高。2.抑制 NF-κB 分子后,ELISA、Western Blot 檢測(cè)到 LV-SKOV-3 細(xì)胞 YKL-40的表達(dá)下降,其細(xì)胞上清分泌水平為(25.40±3.30)ng/ml,是DMSO對(duì)照組的0.64倍。其細(xì)胞YKL-40蛋白的相對(duì)表達(dá)量為DMSO組的0.68倍。3.經(jīng)不同濃度DDP處理后,CCK-8檢測(cè)均表現(xiàn)為細(xì)胞LV-SKOV-3的抑制率較NC-SKOV-3降低。這說(shuō)明,YKL-40過(guò)表達(dá)可降低DDP對(duì)卵巢癌細(xì)胞SKOV-3的殺傷力。4.抑制NF-κB后,在各濃度梯度DDP作用下,抑制劑組LV-SKOV-3細(xì)胞的抑制率較DMSO組增高,但仍低于NC-SKOV-3細(xì)胞組。這說(shuō)明,抑制NF-κB可部分恢復(fù)順鉑對(duì)SKOV-3細(xì)胞的殺傷力。[結(jié)論]1.NF-κB可調(diào)控上皮性卵巢癌SKOV-3細(xì)胞中YKL-40的表達(dá)。2.YKL-40可降低上皮性卵巢癌SKOV-3細(xì)胞鉑類藥物的敏感性,且這一過(guò)程部分受到NF-κB因子的調(diào)控。
[Abstract]:Ovarian cancer is one of the three most common gynecologic malignant tumor, epithelial ovarian cancer (EOC) is the main pathological type (more than 85%), the highest mortality of tumor related death in women with epithelial ovarian cancer. The first high degree of malignancy, early symptoms and occult, prone to invasion and metastasis, resulting in 70% of the patients at the time of diagnosis is occurred in the pelvic organ invasion and dissemination and (or) distant metastasis of organs. At present, the greatest degree of surgical cytoreductive surgery and postoperative chemotherapy of paclitaxel combined with platinum, is the main method for the treatment of epithelial ovarian cancer, and can make the most of the patients in remission. But there is still a relapse in patients with advanced 75%-80% after treatment, the acquired resistance occurred repeatedly during chemotherapy and after in reduced to platinum as first-line chemotherapy drug sensitivity. High invasive characteristics and the emergence of multidrug resistance in epithelial ovarian cancer, is An important cause of hindering the prognosis of the patients, patients with high mortality, a serious threat to women's health. Therefore, to explore and illustrate the effects of molecules involved in ovarian cancer metastasis and chemical resistance and mechanism of.YKL-40 has an important significance, also known as chitinase 3 1 (CHI3L1), is a secreted glycoprotein in breast cancer, lung cancer and, high expression of brain glioma and other malignant tumors. Studies show that YKL-40 may be involved in malignant glioma through a variety of mechanisms, endometrial cancer and other tumor cell invasion and metastasis. Another study confirmed that YKL-40 molecules can guide resistance to temozolomide via the AKT/ERK pathway (TMZ) of brain glioma cells strain (TMZ-R U87) resistance to temozolomide. However, whether YKL-40 can influence the migration ability of EOC cells and the sensitivity to platinum drugs, also is not clear. This research used the EOC cell line SKOV-3 classic as the research object, Is divided into three parts, respectively from the in vitro validation of YKL-40 molecules on epithelial ovarian cancer cell migration and the effects of platinum drug sensitivity, and to explore the related regulatory factors. The first part of YKL-40 in the expression of SKOV-3 [Objective] to detect EOC cells of ovarian cancer SKOV-3 cells in YKL-40 molecule expression. Methods with glioblastoma U87 cells were used as positive control, using RT-PCR, ELISA, Western Blot test, the expression level of SKOV-3 cells. The results from the detection of mRNA and protein levels in YKL-40 in the positive control U87 cells, RT-PCR and ELISA can detect the expression of YKL-40 significantly, the agarose gel electrophoresis showed YKL-40 mRNA amplification, expression the supernatant secretion was (18.41 + 1.69) ng/mL; while in SKOV-3 cells, whether mRNA or protein level was not detected. Conclusion the expression of YKL-40]YKL-40 in SKOV-3 cells No significant cell expression. In the second part, the influence of YKL-40 on migration of ovarian cancer SKOV-3 cells in vitro [Objective] to explore the method. The effect of YKL-40 on the migration ability of EOC cells SKOV-3 in vitro and its molecular mechanism. According to the first part of the detection result, construct YKL-40 lentivirus expressing, using lentivirus infection constructed over expression SKOV-3 cell line LV-SKOV-3 cell YKL-40, empty vector and negative control cell lines NC-SKOV-3, qRT-PCR, ELISA, Western Blot confirmed the YKL-40 over expression; Transwell test to detect the effect of overexpression of YKL-40 on the migration ability of SKOV-3; the specific inhibitor of p38 pathway in cell block MAPK expression changes. Results the ability to detect cell migration]1. successfully constructed YKL-40 the expression of LV-SKOV-3 cells and empty vector control cells NC-SKOV-3.qRT-PCR, ELISA, Western Blot LV-SKOV-3 was detected in YKL-40 cells The expression was significantly enhanced and the relative expression amount of mRNA was 9.89 times higher than that of NC-SKOV-3 cells, protein secretion of (32.35 + 1.38) ng/ml, the number of NC-SKOV-3 cell migration of.2.LV-SKOV-3 cells was 17.43 times the average (255.75 + 12.75) / field, NC-SKOV-3 cells (119.25 + 13.25) / field in.LV-SKOV-3 cells the number of up to 1.14 times the migration of.3. empty vector negative control cells inhibition of p38 MAPK pathway, the migration ability of.Transwell test of down-regulation of LV-SKOV-3 in migration inhibitor group in LV-SKOV-3 cells compared with DMSO control group, the control group 63.30%.[conclusion]YKL-40 can significantly enhance the migration of epithelial ovarian cancer SKOV-3 cells. And this effect may be mediated by p38 MAPK pathway. In the third part, the influence of YKL-40 on sensitivity of ovarian cancer SKOV-3 cells [Objective] to investigate the chemotherapy of ovarian YKL-40 The expression of NF- kappa B. Molecular cancer SKOV-3 cells influence the sensitivity of platinum and related molecular mechanism of]Western Blot test in LV-SKOV-3 cells; NF- kappa B inhibitor, ELISA, Blot detection of NF- regulation of Western kappa B on the expression of SKOV-3 protein in YKL-40 cells; were collected with different concentrations (1 g/ml, 2.5 g/ml, 5 g/ml, 1 g/ml) and cisplatin (DDP) treatment of YKL-40 cells overexpressing LV-SKOV-3 and empty vector negative control NC-SKOV-3 cell 48h, CCK-8 test cell inhibition rate; inhibitor Bay11-7082 specific inhibition of LV-SKOV-3 cells in NF- kappa B, CCK-8 test results. LV-SKOV-3 cells again change the sensitivity to DDP the results show]1.Western Blot, LV-SKOV-3 cells expression of NF- kappa B protein levels compared with negative control NC-SKOV-3 cells increased.2. inhibition of NF- kappa B molecules, ELISA, Western Blot detected LV-SKOV-3 cell YKL- 40 drop in expression, its secretion level of cell supernatant (25.40 + 3.30) ng/ml, DMSO is 0.64 times higher than the control group. The cell YKL-40 expression of the protein is 0.68 times.3. in group DMSO were treated with different concentrations of DDP, CCK-8 detection showed inhibitory rate of LV-SKOV-3 cells is lower than NC-SKOV-3. This shows that YKL-40, over expression of DDP can be reduced on ovarian cancer cells SKOV-3.4. inhibition of NF- kappa B after the destruction, in the different concentration of DDP, the inhibition rate of LV-SKOV-3 cells was higher than that of DMSO group, but still lower than NC-SKOV-3 cell group. This shows that the inhibition of NF- kappa B partially restored cisplatin on SKOV-3 cell killing. Conclusion]1.NF- kappa B can express.2.YKL-40 YKL-40 regulation of epithelial ovarian cancer cell SKOV-3 can reduce the sensitivity of epithelial ovarian cancer cell SKOV-3 platinum drugs, and this process is regulated by NF- factor kappa B.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R737.31

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