本文選題：TRIM24 + 膠質(zhì)細(xì)胞瘤　； 參考：《第四軍醫(yī)大學(xué)》2014年博士論文

【摘要】：膠質(zhì)細(xì)胞瘤包括星形膠質(zhì)細(xì)胞瘤、少突膠質(zhì)細(xì)胞瘤、室管膜瘤以及混合型膠質(zhì)細(xì)胞瘤等。中樞神經(jīng)系統(tǒng)最常見(jiàn)的原發(fā)惡性腫瘤是惡性膠質(zhì)細(xì)胞瘤，涵蓋間變型星形細(xì)胞瘤(WHO Ⅲ級(jí))、間變型少突膠質(zhì)細(xì)胞瘤(WHO Ⅲ級(jí))和多形性膠質(zhì)母細(xì)胞瘤(也稱(chēng)膠質(zhì)母細(xì)胞瘤，WHO Ⅳ級(jí))。大多數(shù)惡性膠質(zhì)細(xì)胞瘤是膠質(zhì)母細(xì)胞瘤。盡管近年來(lái)手術(shù)技術(shù)、放療策略和化療方案取得了重大進(jìn)展，間變型星形細(xì)胞瘤患者的中位總存活期為2-3年，間變型少突膠質(zhì)細(xì)胞瘤患者中位總存活期為3-5年，而膠質(zhì)母細(xì)胞瘤患者中位總存活期僅為12-15個(gè)月。因此，惡性膠質(zhì)細(xì)胞瘤成為腫瘤研究領(lǐng)域的迫切課題。腫瘤標(biāo)志物的鑒定可以提高預(yù)后評(píng)估的準(zhǔn)確度，增加常規(guī)治療的效率，并且開(kāi)拓了分子靶向療法。 TRIM24(tripartite motif-containing24)也被稱(chēng)為T(mén)IF1(transcription intermediaryfactor1)，是轉(zhuǎn)錄中介因子家族的創(chuàng)始成員。TRIM24蛋白的氨基末端有TRIM模體，即RING結(jié)構(gòu)域、B盒和回旋卷曲區(qū)，羧基末端有PHD和Bromo結(jié)構(gòu)域。其中，具有泛素-蛋白連接酶E3活性的RING結(jié)構(gòu)域能介導(dǎo)p53的泛素化降解，而PHD和Bromo結(jié)構(gòu)域識(shí)別特定修飾的組蛋白分子。此外，TRIM24蛋白中間段的LxxLL序列能夠配體依賴(lài)性地結(jié)合多種細(xì)胞核受體，而PxVxL序列可以結(jié)合HP1參與染色質(zhì)結(jié)構(gòu)改造。由于其蛋白結(jié)構(gòu)的多樣性，TRIM24與腫瘤的密切關(guān)系在近些年被逐漸揭示。對(duì)于肝癌，TRIM24是作為抑癌基因；但對(duì)于粒細(xì)胞白血病和乳腺癌，TRIM24則發(fā)揮癌基因功能。 比較基因組雜交實(shí)驗(yàn)已發(fā)現(xiàn)大約1/3的膠質(zhì)母細(xì)胞瘤存在TRIM24基因片段的擴(kuò)增，尤其是對(duì)于50歲以上的患者，提示TRIM24可能參與了膠質(zhì)細(xì)胞瘤的發(fā)生和發(fā)展。為了闡明它們之間可能存在的關(guān)系，我們收集手術(shù)標(biāo)本檢測(cè)TRIM24表達(dá)水平，開(kāi)展一系列體外和體內(nèi)實(shí)驗(yàn)以研究其細(xì)胞分子機(jī)理，并探索相關(guān)的臨床意義。 1. TRIM24在膠質(zhì)細(xì)胞瘤中的過(guò)表達(dá)呈現(xiàn)病理級(jí)別依賴(lài)性的特征并且參與膠質(zhì)母細(xì)胞瘤的復(fù)發(fā) 免疫組化方法檢測(cè)TRIM24在15例正常腦組織、24例毛細(xì)胞型星形細(xì)胞瘤(WHOⅠ級(jí))、57例彌漫型星形細(xì)胞瘤(WHOⅡ級(jí))、63例間變型星形細(xì)胞瘤、297例初診膠質(zhì)母細(xì)胞瘤、48例復(fù)發(fā)性膠質(zhì)母細(xì)胞瘤以及44例少突膠質(zhì)細(xì)胞瘤中的表達(dá)情況。在正常腦膠質(zhì)組織和少突膠質(zhì)細(xì)胞瘤中，TRIM24免疫染色陰性或僅在少數(shù)細(xì)胞中顯示弱染色；但是在星形細(xì)胞瘤中，TRIM24呈現(xiàn)過(guò)表達(dá)，并且隨著病理級(jí)別的升高，其表達(dá)量也相應(yīng)增加，只是在毛細(xì)胞型星形細(xì)胞瘤和彌漫型星形細(xì)胞瘤之間未見(jiàn)統(tǒng)計(jì)學(xué)差異。通過(guò)Westernblot檢測(cè)冷凍保存組織標(biāo)本中的蛋白含量，進(jìn)一步驗(yàn)證了免疫組化所觀察到的TRIM24表達(dá)譜。將取自同一患者的初診和復(fù)發(fā)性膠質(zhì)母細(xì)胞瘤標(biāo)本進(jìn)行配對(duì)分析發(fā)現(xiàn)，TRIM24的表達(dá)在膠質(zhì)母細(xì)胞瘤復(fù)發(fā)時(shí)有所升高，尤其是對(duì)于初診時(shí)表達(dá)水平相對(duì)較低的病例。這些結(jié)果提示，TRIM24可能參與了膠質(zhì)細(xì)胞瘤的發(fā)生，并且其表達(dá)水平與膠質(zhì)細(xì)胞瘤的惡性程度之間存在著正相關(guān)關(guān)系。 2. TRIM24表達(dá)水平與初診膠質(zhì)母細(xì)胞瘤患者的預(yù)后具有負(fù)相關(guān)關(guān)系 隨訪工作從2009年開(kāi)始，不斷納入病例并且更新資料，直至2013年結(jié)束，共記錄了297例初診膠質(zhì)母細(xì)胞瘤患者的年齡、性別、手術(shù)切除程度、KPS評(píng)分、化療狀態(tài)、總生存期(overall survival, OS)和無(wú)進(jìn)展生存期(progression-free survival，PFS)等數(shù)據(jù)。采用Kaplan-Meier法繪制TRIM24低表達(dá)組和高表達(dá)組患者的生存曲線得出：低表達(dá)組的中位OS為13.9個(gè)月(95%CI，11.5-16.3個(gè)月)，而高表達(dá)組的中位OS為11.0個(gè)月(95%CI，10.6-11.4個(gè)月)；低表達(dá)組的中位PFS為6.5個(gè)月(95%CI，5.5-7.5個(gè)月)，而高表達(dá)組的中位PFS為5.3個(gè)月(95%CI，4.8-5.8個(gè)月)。log-rank檢驗(yàn)發(fā)現(xiàn)低表達(dá)組和高表達(dá)組的OS和PFS之間均存在顯著性差異(P＜0.001)。多因素Cox比例風(fēng)險(xiǎn)回歸模型發(fā)現(xiàn)，KPS評(píng)分、年齡和TRIM24表達(dá)水平三者是影響OS的獨(dú)立預(yù)后因素，而KPS評(píng)分和TRIM24水平還是PFS的獨(dú)立預(yù)后影響因素。這些結(jié)果提示，檢測(cè)惡性標(biāo)志物TRIM24的水平，并結(jié)合患者臨床指標(biāo)綜合考慮，在一定程度上可以提高膠質(zhì)母細(xì)胞瘤患者預(yù)后評(píng)估的準(zhǔn)確度；同時(shí)進(jìn)一步說(shuō)明了對(duì)于高度異質(zhì)性的單一病理級(jí)別的膠質(zhì)細(xì)胞瘤——膠質(zhì)母細(xì)胞瘤，TRIM24水平與腫瘤惡性程度之間仍然存在著正相關(guān)關(guān)系。 3. TRIM24在體外和體內(nèi)條件下促進(jìn)膠質(zhì)細(xì)胞瘤生長(zhǎng) 為了研究TRIM24促進(jìn)膠質(zhì)細(xì)胞瘤惡性進(jìn)展的機(jī)理，我們構(gòu)建了2種TRIM24干涉逆轉(zhuǎn)錄病毒、1種陰性對(duì)照逆轉(zhuǎn)錄病毒、過(guò)表達(dá)人TRIM24基因慢病毒以及陰性對(duì)照慢病毒，并將這些病毒感染人膠質(zhì)母細(xì)胞瘤細(xì)胞系，從而檢測(cè)TRIM24表達(dá)水平改變對(duì)膠質(zhì)細(xì)胞瘤生長(zhǎng)的影響。細(xì)胞增殖曲線顯示，干涉TRIM24表達(dá)延長(zhǎng)了T98和U87細(xì)胞的倍增時(shí)間。流式細(xì)胞儀測(cè)定細(xì)胞周期分布發(fā)現(xiàn)，TRIM24干涉的T98細(xì)胞的G2/M期比例減少，而過(guò)表達(dá)TRIM24的U251細(xì)胞的G2/M期比例增加。軟瓊脂克隆形成實(shí)驗(yàn)得出，TRIM24干涉的T98和U87細(xì)胞形成的克隆不僅數(shù)量減少，，而且體積縮小。體內(nèi)實(shí)驗(yàn)發(fā)現(xiàn)，穩(wěn)定干涉TRIM24表達(dá)的T98細(xì)胞喪失了裸鼠皮下成瘤能力，而陰性對(duì)照細(xì)胞仍然具有成瘤性。這些結(jié)果表明，TRIM24能夠促進(jìn)膠質(zhì)細(xì)胞瘤的生長(zhǎng)，所以針對(duì)TRIM24的靶向治療有望起到干擾膠質(zhì)細(xì)胞瘤進(jìn)一步發(fā)展的作用。 4. TRIM24通過(guò)激活PI3K/Akt信號(hào)轉(zhuǎn)導(dǎo)促進(jìn)膠質(zhì)細(xì)胞瘤生長(zhǎng) 由于PI3K/Akt和Raf/MEK/ERK信號(hào)轉(zhuǎn)導(dǎo)途徑是與膠質(zhì)細(xì)胞瘤生長(zhǎng)相關(guān)的主要通路，故采用Western blot檢測(cè)TRIM24干涉對(duì)Akt和ERK活化程度的影響，并進(jìn)行TRIM24表達(dá)恢復(fù)實(shí)驗(yàn)。干涉TRIM24表達(dá)引起p-Akt水平降低，同時(shí)p-ERK水平升高，反映了由于p-Akt減少后對(duì)Raf/MEK/ERK通路的抑制作用得到緩解。當(dāng)TRIM24干涉的細(xì)胞感染過(guò)表達(dá)TRIM24的慢病毒時(shí)，TRIM24含量有一定程度的恢復(fù)，原先降低的p-Akt水平有所上升，而原先升高的p-ERK水平則有所回落。MTT實(shí)驗(yàn)發(fā)現(xiàn)，與TRIM24低表達(dá)細(xì)胞相比，TRIM24高表達(dá)細(xì)胞的增殖對(duì)PI3K抑制劑LY294002和針對(duì)PIK3CA的siRNA更加敏感。Real-time RT-PCR和Western blot檢測(cè)發(fā)現(xiàn)，當(dāng)干涉TRIM24表達(dá)時(shí)，PIK3CA表達(dá)水平下調(diào)。ChIP實(shí)驗(yàn)顯示，TRIM24蛋白能夠結(jié)合T98和U87細(xì)胞中PIK3CA基因的啟動(dòng)子。野生型TRIM24能夠在一定程度上恢復(fù)TRIM24干涉細(xì)胞的PIK3CA和p-Akt水平，而PHD-Bromo段缺失的TRIM24突變體則未見(jiàn)效果。這些結(jié)果說(shuō)明，TRIM24對(duì)膠質(zhì)細(xì)胞瘤生長(zhǎng)的促進(jìn)作用是由PI3K/Akt信號(hào)通路所介導(dǎo)。 5. TRIM24促進(jìn)膠質(zhì)細(xì)胞瘤的耐藥性 除了腫瘤生長(zhǎng)，耐藥是惡性膠質(zhì)細(xì)胞瘤進(jìn)展和復(fù)發(fā)的重要因素。為了研究TRIM24是否影響細(xì)胞對(duì)替莫唑胺的反應(yīng)性，我們將TRIM24干涉和陰性對(duì)照細(xì)胞分別暴露于替莫唑胺作用之下。MTT實(shí)驗(yàn)發(fā)現(xiàn)，干涉TRIM24表達(dá)可以增加替莫唑胺對(duì)T98和U87細(xì)胞的毒性。平板克隆形成實(shí)驗(yàn)顯示，TRIM24干涉削弱了膠質(zhì)瘤細(xì)胞在替莫唑胺作用下形成克隆的能力。將TRIM24干涉的T98細(xì)胞暴露于替莫唑胺1周后，可見(jiàn)明顯的caspase-7剪切活化體、TUNEL標(biāo)記信號(hào)以及Annexin V著色，而對(duì)照組細(xì)胞卻很少有凋亡發(fā)生。體內(nèi)實(shí)驗(yàn)同樣發(fā)現(xiàn)TRIM24干涉能夠提高替莫唑胺的治療效果。而且，在臨床背景下，TRIM24低表達(dá)的膠質(zhì)母細(xì)胞瘤患者能夠從化療中獲益，而TRIM24高表達(dá)組患者的預(yù)后不會(huì)因?yàn)榛煻兴淖�。這些結(jié)果說(shuō)明，TRIM24可以促進(jìn)膠質(zhì)細(xì)胞瘤的耐藥性，將TRIM24干涉和化療聯(lián)合應(yīng)用有望提高膠質(zhì)母細(xì)胞瘤的治療效果。 6. TRIM24通過(guò)PI3K/Akt/NF-κB信號(hào)轉(zhuǎn)導(dǎo)調(diào)節(jié)耐藥基因MGMT的表達(dá) 由于DNA修復(fù)酶MGMT在替莫唑胺耐藥中發(fā)揮著關(guān)鍵作用，所以我們檢測(cè)了TRIM24干涉對(duì)MGMT的mRNA和蛋白水平的影響。Western blot實(shí)驗(yàn)發(fā)現(xiàn)，TRIM24干涉導(dǎo)致T98細(xì)胞的MGMT蛋白含量減少。Real-time RT-PCR實(shí)驗(yàn)顯示，TRIM24干涉是在轉(zhuǎn)錄水平上調(diào)節(jié)MGMT的表達(dá)。雖然ChIP實(shí)驗(yàn)未見(jiàn)TRIM24結(jié)合MGMT基因啟動(dòng)子，但是雙熒光素酶報(bào)告基因檢測(cè)發(fā)現(xiàn)，TRIM24干涉引起NF-κB轉(zhuǎn)錄活性降低，即與抑制PI3K/Akt信號(hào)轉(zhuǎn)導(dǎo)的結(jié)果類(lèi)似。TRIM24干涉對(duì)MGMT表達(dá)的影響可以被重新引入的TRIM24所逆轉(zhuǎn)，但是如果同時(shí)用siRNA干涉NF-κB亞單位p65的編碼基因RelA的表達(dá)，MGMT水平的恢復(fù)則受到阻斷。這些結(jié)果說(shuō)明，TRIM24對(duì)MGMT表達(dá)的調(diào)控作用是(或者至少部分是)由PI3K/Akt/NF-κB途徑所介導(dǎo)的。
[Abstract]:Glioblastoma includes astrocytoma, oligodendroglioma, ependymoma, and mixed glioblastoma. The most common primary malignant tumor of the central nervous system is malignant glioblastoma, which covers the variant type astrocytoma (WHO grade III), oligodendroglioma (WHO grade III) and glioblastoma. (also known as glioblastoma, WHO IV). Most of the malignant glioblastomas are glioblastoma. Although significant progress has been made in surgical techniques, radiotherapy strategies and chemotherapy schemes in recent years, the median survival time of patients with mesenchymal astrocytoma is 2-3 years, and the median survival time of the patients with oligodendroglioma is 3-5 years, and the glue is in glue. The median survival period of the patients with blastoma is only 12-15 months. Therefore, malignant glioblastoma has become an urgent subject in the field of cancer research. Identification of tumor markers can improve the accuracy of prognosis assessment, increase the efficiency of conventional therapy, and develop molecular targeting therapy.
TRIM24 (tripartite motif-containing24), also known as TIF1 (transcription intermediaryfactor1), is the original member of the transcriptional mediator family, the amino terminal of the amino terminal of the.TRIM24 protein has TRIM modules, namely the RING domain, B box and cyclotron curling area, and the carboxyl terminal has PHD and Bromo domains. The domain can mediate the ubiquitination of p53, while the PHD and Bromo domains identify the specific modified histone molecules. In addition, the LxxLL sequence of the intermediate segment of the TRIM24 protein can be ligands dependent on a variety of nuclear receptors, and the PxVxL sequence can be combined with HP1 to modify the chromatin structure. Because of its protein structure diversity, TRIM24 and swelling The close relationship between tumors has been gradually revealed in recent years. For liver cancer, TRIM24 is a tumor suppressor gene, but for granulocytic leukemia and breast cancer, TRIM24 plays the oncogene function.
Comparative genomic hybridization has found that approximately 1/3 glioblastoma exists TRIM24 gene fragment amplification, especially for patients over 50 years old, suggesting that TRIM24 may be involved in the occurrence and development of glioblastoma. In order to clarify the possible relationship between them, we collect surgical specimens to detect the level of TRIM24 expression and develop A series of in vitro and in vivo experiments were carried out to study the cellular molecular mechanism and explore the clinical relevance.
1. the overexpression of TRIM24 in glioblastoma is pathological grade dependent and participates in the recurrence of glioblastoma.
Immunohistochemical method was used to detect TRIM24 in 15 normal brain tissues, 24 cases of hair cell type astrocytoma (WHO grade I), 57 cases of diffuse astrocytoma (WHO class II), 63 cases of Intervariant astrocytoma, 297 newly diagnosed glioblastoma, 48 recurrent glioblastoma, and 44 oligodendroglioma. In both qualitative and oligodendrogliomas, TRIM24 immunostaining is negative or only a few cells show weak staining. But in astrocytoma, TRIM24 is overexpressed, and its expression increases with the rise of pathological grade, only between the hair cell type astrocytoma and the diffuse astrocytoma. The protein content in the frozen tissue specimens was detected by Westernblot, and the TRIM24 expression profile observed by immunohistochemistry was further verified. The paired analysis of the primary and recurrent glioblastoma specimens from the same patient showed that the expression of TRIM24 increased in the recurrence of glioblastoma, especially in the case of recurrent glioblastoma. These results suggest that TRIM24 may be involved in the occurrence of glioma and that there is a positive correlation between the level of the expression and the malignancy of glioma.
2. the level of TRIM24 expression is negatively correlated with the prognosis of patients with newly diagnosed glioblastoma.
The follow-up work began in 2009 and continued to be included in cases and updated until the end of 2013. A total of 297 patients with newly diagnosed glioblastoma were recorded, including age, sex, surgical excision, KPS, chemotherapy, total survival (overall survival, OS), and progression free survival (progression-free survival, PFS). The an-Meier method was used to draw the survival curve of TRIM24 low expression group and high expression group. The median OS of the low expression group was 13.9 months (95%CI, 11.5-16.3 month), while the middle OS in the high expression group was 11 months (95%CI, 10.6-11.4 month), and the median PFS in the low expression group was 6.5 months (95%CI, 5.5-7.5 month), while the median PFS in the high expression group was 5.3. There was a significant difference between the OS and PFS in the low expression group and the high expression group (P < 0.001). The multiple factor Cox proportional risk regression model found that KPS score, age and TRIM24 expression level three were independent preconditioning factors affecting OS, while KPS score and TRIM24 level were the independent prognostic factors, and the independent prognosis was also found to be an independent prognosis. These results suggest that the detection of the level of the malignant marker TRIM24 and the combination of the patient's clinical indicators can improve the accuracy of the prognosis evaluation of the patients with glioblastoma to a certain extent, and further explain the single pathological grade of glioblastoma, glioblastoma, TRI, which is highly heterogeneous. There is still a positive correlation between the level of M24 and malignancy of tumor.
3. TRIM24 promotes glioma growth in vitro and in vivo.
In order to study the mechanism of TRIM24 to promote the malignant progression of glioblastoma, we constructed 2 kinds of TRIM24 interfering retroviruses, 1 negative control retroviruses, TRIM24 gene lentivirus and negative control lentivirus, and the virus infection of human glioblastoma cell lines, so as to detect the change of TRIM24 expression level to glue The cell proliferation curve showed that interferometric TRIM24 expression extended the doubling time of T98 and U87 cells. Flow cytometry detected cell cycle distribution, the G2/M phase ratio of TRIM24 interfered T98 cells decreased, while the G2/M phase of U251 cells over expressed TRIM24 increased. The soft agar clone formation experiment obtained, TRIM24, TRIM24. The clones formed by interfered T98 and U87 cells are not only reduced in quantity but also in size. In vivo experiments have found that T98 cells that stably interfere with TRIM24 expression have lost the ability to tumour subcutaneously in nude mice, while negative control cells still have tumorigenicity. These results suggest that TRIM24 can promote the growth of glioma, so the targeting of TRIM24 is targeted. Treatment is expected to play a role in further development of glioma.
4. TRIM24 promotes glioma growth by activating PI3K/Akt signal transduction.
As PI3K/Akt and Raf/MEK/ERK signal transduction pathways are the main pathways associated with the growth of glioblastoma, Western blot is used to detect the effect of TRIM24 interference on the activation of Akt and ERK and to restore the TRIM24 expression. The interference TRIM24 expression causes p-Akt level to decrease, and the p-ERK level increases at the same time, reflecting the decrease of p-Akt. The inhibition of the Raf/MEK/ERK pathway was alleviated. When the TRIM24 interfered cells infected the TRIM24's lentivirus, the TRIM24 content was restored to a certain extent, and the previously reduced p-Akt level had increased, while the previously elevated p-ERK level was reduced to the.MTT experiment, and the TRIM24 high expression cells were compared with the TRIM24 low expression cells. The proliferation of the PI3K inhibitor LY294002 and the siRNA for the PIK3CA were more sensitive to.Real-time RT-PCR and Western blot detection. When the interference TRIM24 expression, PIK3CA expression level down.ChIP experiment showed that the TRIM24 protein could combine the promoter and the promoter of the gene. The PIK3CA and p-Akt levels of the cells were interfered, while the TRIM24 mutant of the PHD-Bromo segment was not effective. These results suggest that the promotion of TRIM24 on the growth of glioma is mediated by the PI3K/Akt signaling pathway.
5. TRIM24 to promote the drug resistance of glioma
In addition to tumor growth, drug resistance is an important factor in the progression and recurrence of malignant glioblastoma. In order to study whether TRIM24 affects the reactivity of cells to temozolomide, we found that TRIM24 interference and negative control cells were exposed to the action of temozolomide, respectively, in.MTT experiment. The interference of TRIM24 expression could increase the effect of temozolomide on T98 and U87. TRIM24 interference weakened the ability of glioma cells to form clones under the action of temozolomide. The TRIM24 interfered T98 cells were exposed to temozolomide for 1 weeks, and obvious caspase-7 shear activator, TUNEL marker signal and Annexin V coloring were seen, while few cells in the control group were apoptotic. In vivo experiments also found that TRIM24 interference could improve the therapeutic effect of temozolomide. In the clinical context, patients with TRIM24 low expression of glioblastoma could benefit from chemotherapy, while the prognosis of the TRIM24 high expression group was not altered by chemotherapy. These results suggest that TRIM24 can promote glioblastoma. The combination of TRIM24 interference and chemotherapy is expected to improve the therapeutic effect of glioblastoma.
6. TRIM24 regulates the expression of drug resistance gene MGMT through PI3K/Akt/NF- kappa B signal transduction.
As DNA repair enzyme MGMT plays a key role in the drug resistance of temozolomide, we detected the effect of TRIM24 interference on the mRNA and protein levels of MGMT. The.Western blot experiment found that TRIM24 interference resulted in the decrease of MGMT protein content in T98 cells and.Real-time RT-PCR experiment showed that the interference was at the transcriptional level. Although the ChIP experiment did not see the TRIM24 binding MGMT gene promoter, the double luciferase reporter gene detection found that the TRIM24 interference caused the decrease of NF- kappa B transcriptional activity, that is, the effect of the inhibition of PI3K/Akt signal transduction is similar to that the effect of.TRIM24 interference on MGMT expression can be reversed by the reintroduced TRIM24, but if siRNA interferes with N The expression of the encoding gene RelA of the F- kappa B subunit p65 and the recovery of the MGMT level were blocked. These results suggest that the regulation of TRIM24 on MGMT expression is (or at least partly) mediated by the PI3K/Akt/NF- kappa B pathway.

【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R739.41

【共引文獻(xiàn)】

相關(guān)期刊論文 前10條

1 金晶;王龍勝;;病案點(diǎn)評(píng)[J];安徽醫(yī)學(xué);2009年12期

2 ;Platelet-derived growth factor receptor alpha in glioma:a bad seed[J];癌癥;2011年09期

3 謝云鵬;田甜;申興斌;王維興;錢(qián)濤;;星形細(xì)胞瘤組織TGF-β1、Smad7與VEGF的表達(dá)及意義[J];承德醫(yī)學(xué)院學(xué)報(bào);2011年01期

4 錢(qián)銀鋒;殷敏敏;余永強(qiáng);;擴(kuò)散加權(quán)成像在低級(jí)別膠質(zhì)瘤的鑒別診斷價(jià)值[J];磁共振成像;2010年01期

5 劉新新;韓曉雨;李智勇;苗延巍;;側(cè)腦室內(nèi)未成熟畸胎瘤1例MRI分析[J];磁共振成像;2010年06期

6 王斐斐;程敬亮;趙藝?yán)?張勇;閆晨宇;白潔;張會(huì)霞;崔曉琳;;動(dòng)態(tài)磁敏感對(duì)比MR灌注成像對(duì)腦膜瘤分級(jí)的臨床價(jià)值[J];磁共振成像;2011年01期

7 宋茜;齊悅彤;李瑩;;第三腦室脊索樣膠質(zhì)瘤1例[J];磁共振成像;2011年02期

8 劉才保;康厚藝;周鵬程;肖華亮;張偉國(guó);;椎管內(nèi)彌漫性黑色素細(xì)胞增生癥1例[J];磁共振成像;2011年06期

9 趙君;周俊林;張靜;;不同分級(jí)少突膠質(zhì)細(xì)胞腫瘤的MRI診斷[J];磁共振成像;2012年01期

10 ;Gliomatosis Cerebri[J];Chinese Journal of Clinical Oncology;2008年04期

相關(guān)會(huì)議論文 前10條

1 姜新義;陳亮岑;王霄;沙先誼;方曉玲;;基于整合素受體介導(dǎo)的長(zhǎng)循環(huán)碳酸酯納米粒對(duì)惡性腦膠質(zhì)瘤靶向遞藥研究[A];2011年中國(guó)藥學(xué)大會(huì)暨第11屆中國(guó)藥師周論文集[C];2011年

2 Yuya Yoshida;Mitsutoshi Nakada;Naotoshi Sugimoto;Tomoya Harada;Yasuhiko Hayashi;Daisuke Kita;Naoyuki Uchiyama;Yutaka Hayashi;Akihiro Yachie;Yoh Takuwa;Jun-ichiro Hamada;;Sphingosine-1-phosphate receptor type 1 regulates glioma cell proliferation and correlates with patient survival[A];中國(guó)抗癌協(xié)會(huì)神經(jīng)腫瘤專(zhuān)業(yè)委員會(huì)第八屆學(xué)術(shù)會(huì)議論文集[C];2011年

3 ;Histologic research of microcirculation patterns in human and xengraft model glioblastoma[A];中國(guó)抗癌協(xié)會(huì)神經(jīng)腫瘤專(zhuān)業(yè)委員會(huì)第八屆學(xué)術(shù)會(huì)議論文集[C];2011年

4 Yuya Yoshida;Mitsutoshi Nakada;Tomoya Harada;Shingo Tanaka;Takuya Furuta;Yasuhiko Hayashi;Daisuke Kita;Naoyuki Uchiyama;Yutaka Hayashi;Jun-ichiro Hamada;;The expression level of sphingosine-1-phosphate receptor type 1 is related to MIB-1 labeling index and predicts survival of glioblastoma patients[A];中國(guó)抗癌協(xié)會(huì)神經(jīng)腫瘤專(zhuān)業(yè)委員會(huì)第八屆學(xué)術(shù)會(huì)議論文集[C];2011年

5 朱明月;李偉;夏華;魯琰;董栩;陳h;郭峻莉;符史干;謝協(xié)駒;李孟森;;抑制PI3K信號(hào)促進(jìn)TRAIL誘導(dǎo)人乳腺癌細(xì)胞MCF-7凋亡[A];2013海南省第五屆生命科學(xué)聯(lián)合學(xué)術(shù)會(huì)議論文匯編[C];2013年

6 鄧勇;張煒飛;張成斌;林金明;;液相色譜串聯(lián)質(zhì)譜法定量檢測(cè)前列腺癌細(xì)胞肌氨酸代謝[A];中國(guó)化學(xué)會(huì)第29屆學(xué)術(shù)年會(huì)摘要集——第38分會(huì)：質(zhì)譜分析[C];2014年

7 支修益;;亞肺葉切除治療早期肺癌[A];中國(guó)腫瘤內(nèi)科進(jìn)展 中國(guó)腫瘤醫(yī)師教育（2014）[C];2014年

8 劉后銀;謝明祥;;彌散張量纖維成像在顱內(nèi)腫瘤的應(yīng)用及手術(shù)指導(dǎo)意義[A];2013年貴州省神經(jīng)外科年會(huì)論文集[C];2013年

9 張蕾;王崇薇;史天陸;張圣雨;孫言才;姜玲;;2004-2013年我院腫瘤患者嚴(yán)重藥品不良反應(yīng)分析[A];第十三屆全國(guó)青年藥師成才之路論壇暨抗腫瘤藥物合理應(yīng)用與臨床藥學(xué)實(shí)踐國(guó)家級(jí)繼教會(huì)議論文集[C];2014年

10 鄧勇;張煒飛;張成斌;林金明;;姜黃素對(duì)前列腺癌細(xì)胞肌氨酸代謝和AR/TMPRSS2-ERG信號(hào)通路的影響[A];中國(guó)化學(xué)會(huì)首屆全國(guó)質(zhì)譜分析學(xué)術(shù)研討會(huì)會(huì)議論文集[C];2014年

相關(guān)博士學(xué)位論文 前10條

1 蔣震;神經(jīng)系統(tǒng)腫瘤及瘤周血管的磁共振成像研究[D];蘇州大學(xué);2010年

2 別黎;跨平臺(tái)整合微陣列數(shù)據(jù)篩選與膠質(zhì)瘤級(jí)別相關(guān)基因的實(shí)驗(yàn)研究[D];吉林大學(xué);2011年

3 王春琳;MDM4在人腦膠質(zhì)母細(xì)胞瘤中的表達(dá)與功能研究[D];第二軍醫(yī)大學(xué);2011年

4 陶幫寶;Stathmin在膠質(zhì)細(xì)胞瘤表達(dá)及其化療藥物敏感性研究[D];第二軍醫(yī)大學(xué);2011年

5 李維卿;Med19在星形細(xì)胞瘤中的表達(dá)及對(duì)其惡性生物學(xué)行為調(diào)控的實(shí)驗(yàn)研究[D];第二軍醫(yī)大學(xué);2011年

6 趙世斗;OCT4假基因在膠質(zhì)瘤和乳腺癌中的表達(dá)及其意義的研究[D];山東大學(xué);2011年

7 彭雍;RIP3對(duì)膠質(zhì)母細(xì)胞瘤細(xì)胞增殖、死亡和化療敏感性的作用及其作用機(jī)制的研究[D];中南大學(xué);2011年

8 陳若琨;RAS超家族基因RRP22在星形膠質(zhì)瘤中的表達(dá)及對(duì)其生物學(xué)行為影響[D];中南大學(xué);2011年

9 沈明;負(fù)性共刺激分子B7-H1在A2B5陽(yáng)性人腦膠質(zhì)瘤干細(xì)胞樣細(xì)胞中的負(fù)性調(diào)控作用探討[D];復(fù)旦大學(xué);2011年

10 范薇薇;中國(guó)漢族人群腦膠質(zhì)瘤遺傳易感性研究[D];復(fù)旦大學(xué);2011年

相關(guān)碩士學(xué)位論文 前10條

1 顏偉;人膠質(zhì)瘤中骨橋蛋白功能的初步研究[D];南京醫(yī)科大學(xué);2010年

2 李丹;擴(kuò)散張量成像對(duì)腦惡性膠質(zhì)瘤和轉(zhuǎn)移瘤的鑒別診斷價(jià)值研究[D];鄭州大學(xué);2010年

3 蘇國(guó)軍;人腦星形細(xì)胞瘤細(xì)胞體外化療藥物敏感性實(shí)驗(yàn)研究[D];桂林醫(yī)學(xué)院;2010年

4 陳玉升;膠質(zhì)瘤患者血清OY-TES-1截短蛋白抗體的檢測(cè)及臨床意義分析[D];廣西醫(yī)科大學(xué);2011年

5 陳有林;腦源性神經(jīng)營(yíng)養(yǎng)因子與Neuritin基因在膠質(zhì)瘤中的表達(dá)與意義[D];瀘州醫(yī)學(xué)院;2011年

6 趙瑋;CCNG2在腦膠質(zhì)瘤中的表達(dá)及與化療關(guān)系的實(shí)驗(yàn)研究[D];第二軍醫(yī)大學(xué);2011年

7 劉建莉;顱內(nèi)不同分化血管外皮細(xì)胞瘤的影像與P73因子表達(dá)的相關(guān)性研究[D];蘭州大學(xué);2011年

8 張小林;腦膠質(zhì)瘤中內(nèi)源性大麻素代謝酶的表達(dá)及其與腫瘤病理級(jí)別相關(guān)性的研究[D];福建醫(yī)科大學(xué);2011年

9 王佳寧;顱內(nèi)腫瘤影像與病理對(duì)照研究[D];河北醫(yī)科大學(xué);2011年

10 王書(shū)杰;EGF+61 G/A與腦膠質(zhì)瘤易感性分析[D];復(fù)旦大學(xué);2011年

本文編號(hào)：1808446