本文選題：BRAF(V600E)抑制 + AEBP1　； 參考：《中國科學(xué)技術(shù)大學(xué)》2013年博士論文

【摘要】：在超過50%的黑色素瘤病例中BRAF的第600位纈氨酸突變?yōu)楣劝彼?從而使BRAF持續(xù)激活而獲得激酶活性。近期的臨床資料表明,PLX4032作為一個(gè)潛在的、特異的突變BRAF的抑制劑,在治療這類BRAF(V600E)黑色素瘤中顯示了特別顯著的療效,但是治療之后總是會(huì)出現(xiàn)抗藥性。發(fā)現(xiàn)和了解這種獲得性抗藥性形成機(jī)制將有利于發(fā)展新的治療方法,改善這類BRAF(V600E)黑色素瘤長期使用BRAF抑制劑治療的效果和反應(yīng)。在這里我們報(bào)道在具有BRAF抑制劑PLX4032抗藥性的黑色素瘤中,AEBP1的表達(dá)上調(diào)是其獲得PLX4032抗藥性的主要原因。在具有抗藥性的黑色素瘤中,是因?yàn)镻I3K/AKT-CREB信號(hào)通路的超常激活引起AEBP1的轉(zhuǎn)錄上調(diào)。AEBP1的上調(diào)加速IKBa的降解,從而激活NF-KB。另外,抑制PI3K/AKT-CREB-AEBP1-NF-KB信號(hào)通路能夠很顯著地逆轉(zhuǎn)黑色素瘤細(xì)胞對(duì)于PLX4032抗性的表型。更為重要的是AEBP1的上調(diào)在復(fù)發(fā)的病例中得到驗(yàn)證。因此,所有的結(jié)果揭示了一條新的PI3K/AKT-CREB-AEBP1-NF-KB信號(hào)通路,這條信號(hào)通路的激活促進(jìn)了BRAF(V600E)黑色素瘤獲得對(duì)于BRAF抑制的抗性。說明這條信號(hào)通路,特別是AEBP1可以作為一個(gè)全新的治療靶點(diǎn)用于改善或者治療對(duì)于PLX4032具有抗性的黑色素瘤。 腫瘤抑制因子p53在細(xì)胞受到外界壓力刺激的情況下能夠被激活,通過啟動(dòng)DNA的修復(fù)機(jī)制來保護(hù)細(xì)胞或者在細(xì)胞損傷嚴(yán)重不可修復(fù)時(shí)誘導(dǎo)細(xì)胞凋亡以清除損傷細(xì)胞,從而達(dá)到防止細(xì)胞癌變的目的。腫瘤組織中編碼p53的基因經(jīng)常遭到突變,致使其喪失功能,但是在黑色素瘤中野生型p53廣泛表達(dá)而且表達(dá)的水平很高,這與黑色素瘤這種疾病的惡性程度是相悖的,意味著p53在黑色素瘤中喪失了作為一個(gè)有效的腫瘤抑制因子的功能。這里我們發(fā)現(xiàn)在內(nèi)質(zhì)網(wǎng)壓力情況下,p53蛋白水平被穩(wěn)定而上調(diào),主要表現(xiàn)為核內(nèi)的聚集。在功能上,p53在內(nèi)質(zhì)網(wǎng)壓力下被激活后,選擇性轉(zhuǎn)錄上調(diào)microRNA149*的宿主基因GPC1,從而上調(diào)microRNA149*的表達(dá)。P53介導(dǎo)的microRNA149*的上調(diào)對(duì)于黑色素瘤細(xì)胞適應(yīng)內(nèi)質(zhì)網(wǎng)壓力是必要的,P53或者其介導(dǎo)的microRNA149*的表達(dá)被抑制均顯著影響黑色素瘤細(xì)胞對(duì)于內(nèi)質(zhì)網(wǎng)壓力的抗性。
[Abstract]:In more than 50% of melanoma cases, the 600th Val in BRAF mutated to glutamate, which enabled BRAF to be continuously activated to obtain kinase activity. Recent clinical data suggest that PLX4032, as a potential, specific inhibitor of mutated BRAF, has been shown to be particularly effective in the treatment of this type of BRAFV 600E melanoma, but drug resistance is always present after treatment. The discovery and understanding of the mechanism of acquired drug resistance will be beneficial to the development of new treatment methods and improve the efficacy and response of long-term treatment of melanoma with BRAF inhibitor. We report that the up-regulated expression of AEBP1 in melanoma with BRAF inhibitor PLX4032 resistance is the main reason for obtaining PLX4032 resistance. In drug-resistant melanoma, the activation of PI3K/AKT-CREB signaling pathway leads to the up-regulation of AEBP1 transcription. AEBP1 upregulation accelerates the degradation of IKBa and activates NF-KB. In addition, inhibition of PI3K/AKT-CREB-AEBP1-NF-KB signaling pathway can significantly reverse the PLX4032 resistance phenotype of melanoma cells. More importantly, the upregulation of AEBP1 was confirmed in recurrent cases. Therefore, all the results reveal a new PI3K/AKT-CREB-AEBP1-NF-KB signaling pathway, the activation of which promotes BRAFV 600E) melanoma to acquire resistance to BRAF inhibition. This signal pathway, especially AEBP1, can be used as a new therapeutic target to improve or treat PLX4032 resistant melanoma. Tumor suppressor p53 can be activated when the cells are stimulated by external pressure. It can protect the cells by initiating the repair mechanism of DNA or induce cell apoptosis to clear the damaged cells when the cells are seriously damaged and irreparable. In order to prevent cell carcinogenesis. The genes encoding p53 are often mutated in tumor tissues, resulting in loss of function, but wild type p53 is widely expressed and expressed at a high level in melanoma, which is contrary to the malignancy of melanoma. This means that p53 has lost its function as an effective tumor suppressor in melanoma. We found that p53 protein level was stable and up-regulated under endoplasmic reticulum pressure, mainly in nucleus aggregation. Functionally, p53 was activated under endoplasmic reticulum pressure, Selective transcription upregulated the host gene GPC1 of microRNA149*, thus upregulating the expression of microRNA149*. P53 mediated upregulation of microRNA149* was necessary for melanoma cells to adapt to endoplasmic reticulum pressure, or the inhibition of the expression of microRNA149* mediated by microRNA149* significantly affected black. Resistance of tumor cells to endoplasmic reticulum pressure.
【學(xué)位授予單位】：中國科學(xué)技術(shù)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2013
【分類號(hào)】：R739.5

【引證文獻(xiàn)】

相關(guān)博士學(xué)位論文 前1條

1 王啟明;基于聚谷氨酸構(gòu)象轉(zhuǎn)變構(gòu)建納米靶向復(fù)合膠束及其抗黑色素瘤研究[D];北京協(xié)和醫(yī)學(xué)院;2014年

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本文編號(hào)：1838337