本文選題：ABCG2　切入點(diǎn)：膠質(zhì)瘤干細(xì)胞　出處：《蘇州大學(xué)》2015年博士論文　論文類型：學(xué)位論文

【摘要】：目前研究表明,惡性神經(jīng)膠質(zhì)瘤(glioma)簡(jiǎn)稱膠質(zhì)瘤,是中樞神經(jīng)系統(tǒng)最常見的原發(fā)性惡性腫瘤。膠質(zhì)瘤的發(fā)病率約占所有腦部原發(fā)性腫瘤的50%。廣義的膠質(zhì)瘤包含所有神經(jīng)上皮性的腫瘤,狹義的定義僅包含膠質(zhì)細(xì)胞來源的顱內(nèi)腫瘤。膠質(zhì)瘤細(xì)胞具有多源性,包含星形細(xì)胞瘤、少支膠質(zhì)瘤和室管膜瘤等十余種類型。來源不同,腫瘤生物學(xué)行為亦相異。星形膠質(zhì)細(xì)胞瘤是最常見的膠質(zhì)瘤類型,發(fā)病率約占中樞神經(jīng)系統(tǒng)腫瘤的31%,占膠質(zhì)瘤的78%左右。此病男性多見,高發(fā)年齡為30~40歲。發(fā)病部位以大腦顳葉和額葉較為多見。星形膠質(zhì)細(xì)胞瘤亦具有多形性,根據(jù)國(guó)際衛(wèi)生組織(WHO)的分級(jí)標(biāo)準(zhǔn),肥胖型星形細(xì)胞瘤為Ⅱ~Ⅲ級(jí),間變型星形細(xì)胞瘤為Ⅲ級(jí),多形性膠質(zhì)母細(xì)胞瘤(GBM)則為Ⅵ級(jí)。分級(jí)愈高,侵襲性和浸潤(rùn)性愈強(qiáng)。目前,膠質(zhì)瘤的外科治療得到顯著提高,并配合相應(yīng)的放療和化療藥物靶向作用提升,膠質(zhì)瘤的治愈水平已經(jīng)顯著改善。但是由于其具有高度的侵襲性和浸潤(rùn)性,膠質(zhì)瘤患者的總體治愈率仍差強(qiáng)人意。因此,有必要深入的了解膠質(zhì)瘤細(xì)胞惡性腫瘤學(xué)生物行為的相關(guān)分子學(xué)機(jī)制,為今后的靶向治療奠定一定的理論基礎(chǔ)。(ATP-binding cassette sub-family G member 2,ABCG2)亦被稱為乳腺癌抵抗蛋白或者palacental ABC protein/mitoxantrone抵抗蛋白。ABCG2蛋白隸屬于ATP結(jié)合的cassette轉(zhuǎn)運(yùn)子家族。這一家族是成員最多和最為古老的轉(zhuǎn)運(yùn)子組成單位,具有高度的進(jìn)化保守性和物種間同質(zhì)性�，F(xiàn)已證實(shí):包含胰腺、肝臟、小腸和直腸在內(nèi)的多種組織內(nèi)均存在ABCG2蛋白的表達(dá)。此外,ABCG2蛋白在神經(jīng)膠質(zhì)瘤細(xì)胞、乳腺癌細(xì)胞和肺癌細(xì)胞表面存在過表達(dá)現(xiàn)象。新近,有研究報(bào)道:在多種干細(xì)胞表面觀測(cè)到有ABCG2蛋白的表達(dá),并具有高度相似性;此外,ABCG2蛋白亦被認(rèn)為是一種調(diào)控干細(xì)胞發(fā)生“side-population”行為的關(guān)鍵分子。因此,不少研究者認(rèn)為:ABCG2蛋白可能是一種非常有效的腫瘤干細(xì)胞標(biāo)志物。通過調(diào)控ABCG2基因的表達(dá),也許能夠影響腫瘤細(xì)胞的生物學(xué)行為。已有研究表明,下調(diào)ABCG2的表達(dá)能夠抑制結(jié)直腸癌細(xì)胞和腎母細(xì)胞瘤細(xì)胞的增殖、遷移和浸潤(rùn)能力。但是,abcg2基因調(diào)控和神經(jīng)膠質(zhì)細(xì)胞瘤的惡性生物學(xué)行為之間的關(guān)系,尚未得到充分闡明�；|(zhì)金屬蛋白酶(matrixmetalloproteinases,mmps)隸屬于鋅依賴性內(nèi)肽酶家族。目前,在人體內(nèi),已被證實(shí)存在23位成員。mmps是促進(jìn)細(xì)胞外基質(zhì)(ecm)和細(xì)胞基底膜降解的主要酶類。ecm和細(xì)胞基底膜是調(diào)控單個(gè)細(xì)胞同細(xì)胞周圍環(huán)境相互作用,以及多細(xì)胞和多組織間協(xié)同發(fā)育的重要媒介。因此,mmps在多種細(xì)胞生物學(xué)過程中均發(fā)揮了重要作用,這其中就包括腫瘤細(xì)胞的遷移和浸潤(rùn)�，F(xiàn)已證實(shí):mmp9活性增高與gbm細(xì)胞遷移和浸潤(rùn)性增強(qiáng)密切相關(guān)。新近,一項(xiàng)關(guān)于mmp9活性抑制劑,marimastat,聯(lián)合化療的臨床研究已在gbm患者中開展。因此,有理由認(rèn)為進(jìn)一步深入了解mmps促進(jìn)gbm發(fā)病機(jī)制和研制針對(duì)于mmps活性的靶向治療技術(shù),將可能有效提高gbm治療水平。目的:1.研究abcg2基因?qū)d133陽性的u251干細(xì)胞增殖、遷移和侵襲性的影響,為膠質(zhì)瘤的治療提供理論依據(jù)。2.探討abcg2蛋白表達(dá)水平與mmps的表達(dá)及其活性的關(guān)系,進(jìn)一步揭示下調(diào)abcg2蛋白表達(dá)抑制gbm侵襲的分子學(xué)機(jī)制。方法:1.培養(yǎng)u251細(xì)胞系,免疫磁珠法分離cd133陽性細(xì)胞。分別使用abcg2-sirna和abcg2過表達(dá)質(zhì)粒轉(zhuǎn)染u251細(xì)胞,構(gòu)建abcg2蛋白低表達(dá)和過表達(dá)模型。2.在給予cd133陽性u(píng)251細(xì)胞abcg2-sirna和abcg2過表達(dá)質(zhì)粒轉(zhuǎn)染后,觀察abcg2蛋白低表達(dá)和高表達(dá)情況下,分別使用mtt、transell法和細(xì)胞劃痕法測(cè)定細(xì)胞增殖、侵襲和遷移的變化。3.在給予cd133陽性u(píng)251細(xì)胞abcg2-sirna和abcg2過表達(dá)質(zhì)粒轉(zhuǎn)染后,abcg2蛋白低表達(dá)和高表達(dá)情況下,elisa法和pcr法分別測(cè)定mmp9蛋白和mrna的表達(dá),采用明膠酶譜法測(cè)定mmp9的活性的改變。結(jié)果:1.在給予cd133陽性u(píng)251細(xì)胞abcg2-sirna后,abcg2蛋白和mrna表達(dá)明顯減少。而給予cd133陽性u(píng)251細(xì)胞abcg2過表達(dá)質(zhì)粒轉(zhuǎn)染后,可以發(fā)現(xiàn)ABCG2蛋白和mRNA表達(dá)明顯增加。2.在給予CD133陽性U251細(xì)胞ABCG2-siRNA后,伴隨ABCG2蛋白表達(dá)減少,U251細(xì)胞的增殖、浸潤(rùn)和遷移受到明顯抑制。而給予CD133陽性U251細(xì)胞ABCG2過表達(dá)質(zhì)粒轉(zhuǎn)染后伴隨ABCG2蛋白表達(dá)增加,U251細(xì)胞的增殖、浸潤(rùn)和遷移顯著增強(qiáng)。3.給予CD133陽性U251細(xì)胞ABCG2-siRNA和ABCG2過表達(dá)質(zhì)粒轉(zhuǎn)染,雖然能夠改變ABCG2蛋白的表達(dá),但是并不影響MMP9蛋白和mRNA的合成。在給予CD133陽性U251細(xì)胞ABCG2-siRNA后,伴隨ABCG2蛋白表達(dá)減少,U251干細(xì)胞MMP9活性顯著降低。在給予CD133陽性U251細(xì)胞過表達(dá)質(zhì)粒后,伴隨ABCG2蛋白表達(dá)增加,U251干細(xì)胞MMP9活性顯著增強(qiáng)。結(jié)論:1.下調(diào)U251干細(xì)胞ABCG2蛋白的表達(dá),能夠有效抑制U251干細(xì)胞增殖、浸潤(rùn)和遷移。2.ABCG2基因表達(dá)調(diào)控對(duì)U251干細(xì)胞侵襲分子機(jī)制可能是由于其對(duì)MMP9活性的影響。
[Abstract]:The present study showed that malignant glioma (referred to as glioma) is the central nervous system of glioma, the most common primary malignant tumors. Glioma incidence of all brain glioma primary tumor of the generalized 50%. contains all neural epithelial tumors, narrow definition contains only glial origin intracranial tumors. Gliomas are heterogeneous, including astrocytomas, OLS and ependymoma. Ten types of different sources, the biological behavior of the tumor is different. Astrocytoma glioma is the most common type, incidence of tumors of the central nervous system in 31%, accounting for glioma 78%. The male, age 30~40 years old. The lesion on temporal lobe and frontal brain is more common. Astrocytoma is pleomorphic, according to the World Health Organization (WHO) classification standard, obesity Astrocytoma II ~ III anaplastic astrocytoma grade III, glioblastoma multiforme (GBM) for grade vi. Higher grade, invasive and invasive stronger. At present, surgical treatment of glioma is significantly improved, and the radiotherapy and chemotherapy drugs to enhance the role of glioma, the cure level has been significantly improved. But because of its highly invasive and invasive glioma patients, the overall cure rate is just passable. Therefore, it is necessary to further understand the molecular biological behavior of malignant glioma cells oncology learning mechanism, lay a theoretical foundation for future target to treat (ATP-binding cassette sub-family G. Member 2, ABCG2) also known as breast cancer resistance protein or palacental ABC protein/mitoxantrone resistance protein.ABCG2 protein belonging to cassette transporter family. This combination of ATP A family member is the largest and oldest transporter unit, are highly conserved between species and nature. It has been proved that contains the pancreas, liver, intestine and rectum, the expression of ABCG2 protein were found in other tissues. In addition, ABCG2 protein in glioma cells, the surface of breast cancer cells and lung cancer over expression of the cells. Recently, studies have reported that in a variety of stem cell surface observed the expression of ABCG2 protein, and a high degree of similarity; in addition, ABCG2 protein is also considered to be a key molecular regulation of stem cells "side-population" behavior. Therefore, many researchers believe that ABCG2 protein may be: a very effective tumor stem cell marker. By regulating the expression of ABCG2 gene, may influence the biological behavior of tumor cells. Studies have shown that can down regulate the expression of ABCG2 Inhibition of colorectal cancer cells and Wilms tumor cell proliferation, migration and invasion ability. However, the relationship between ABCG2 gene and the biological behavior of malignant glial cell tumors, has not been fully elucidated. Matrix metalloproteinases (matrixmetalloproteinases, MMPs) belong to the zinc dependent peptidase family. At present, in the human body that has been confirmed the existence of 23 members of.Mmps is to promote the extracellular matrix (ECM) cells and basement membrane degradation enzyme.Ecm and cell membrane is the regulation of individual cells with cell environment interactions, as well as an important medium and multi Organization collaborative multicellular development. Therefore, MMPs in a variety of cell biology plays an important role, including the migration and infiltration of tumor cells. It has been proved that the activity of MMP9 increased the migration and invasive enhancement is closely related to GBM cells. Recently, a On the activity of MMP9 inhibitor, Marimastat, clinical study of combination chemotherapy has been carried out in GBM patients. Therefore, there is reason to believe that further in-depth understanding of the pathogenesis and development of MMPs GBM in the MMPs activity of targeted therapy could effectively promote technology, improve the management level of GBM. Objective: 1. to study the ABCG2 gene on the proliferation of CD133 cells U251 positive effects of migration and invasion of the relationship, and provide a theoretical basis for the expression and activity of.2. on the expression level of ABCG2 protein and MMPs for the treatment of malignant glioma, further reveal the molecular mechanism of inhibiting the down-regulation of ABCG2 protein expression in GBM invasion. Methods: 1. U251 cells, CD133 positive cells were isolated by immunomagnetic beads. Using abcg2-sirna and ABCG2 expression plasmids were transfected into U251 cells, the construction of low expression of ABCG2 protein and expression of.2. in abcg2-sirna and ABCG2 model to CD133 positive U251 cells in table As plasmid after transfection, to observe ABCG2 protein low expression and high expression, respectively, using MTT, the cell proliferation was measured by transell assay and cell scratch assay, invasion and migration of.3. in abcg2-sirna and ABCG2 to change the CD133 + U251 cells expression plasmid transfected, ABCG2 protein low expression and high expression, the expression of MMP9 protein and mRNA was determined by ELISA method and PCR method respectively, using the MMP9 spectrum method for determination of gelatinase activity changes. Results: 1. in CD133 positive U251 cells after abcg2-sirna, the expression of ABCG2 and mRNA decreased significantly. Given CD133 positive U251 cells ABCG2 expression plasmid transfected, the expression of ABCG2 and mRNA can be found obviously increased.2. in CD133 positive U251 cells with ABCG2-siRNA, ABCG2 protein expression decreased, U251 cell proliferation, invasion and migration was inhibited. Given CD133 positive U251 cells ABCG2 With the increased expression of ABCG2 expression plasmid after transfection, U251 cell proliferation, invasion and migration of.3. to ABCG2-siRNA and ABCG2 significantly enhanced CD133 positive U251 cells overexpressing plasmid transfection, although able to change the expression of ABCG2 protein, but does not affect the synthesis of MMP9 protein and mRNA in CD133 positive U251 cells. After ABCG2-siRNA, with ABCG2 protein the reduced expression of U251 stem cells, MMP9 activity was significantly decreased. In CD133 + U251 cells expression plasmid, with increased expression of ABCG2, U251 stem cells MMP9 activity was significantly enhanced. Conclusion: the expression of U251 ABCG2 protein 1. stem cells, can effectively inhibit the proliferation of U251 stem cells, invasion and migration of.2.ABCG2 gene expression regulation the molecular mechanism of U251 stem cell invasion may be due to its effect on MMP9 activity.

【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R739.41

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