黑色素瘤治疗的抗药性机制研究

发布时间：2018-05-03 11:37

本文选题：BRAF(V600E)抑制 + AEBP1　；参考：《中国科学技术大学》2013年博士论文

【摘要】：在超过50%的黑色素瘤病例中BRAF的第600位缬氨酸突变为谷氨酸,从而使BRAF持续激活而获得激酶活性。近期的临床资料表明,PLX4032作为一个潜在的、特异的突变BRAF的抑制剂,在治疗这类BRAF(V600E)黑色素瘤中显示了特别显著的疗效,但是治疗之后总是会出现抗药性。发现和了解这种获得性抗药性形成机制将有利于发展新的治疗方法,改善这类BRAF(V600E)黑色素瘤长期使用BRAF抑制剂治疗的效果和反应。在这里我们报道在具有BRAF抑制剂PLX4032抗药性的黑色素瘤中,AEBP1的表达上调是其获得PLX4032抗药性的主要原因。在具有抗药性的黑色素瘤中,是因为PI3K/AKT-CREB信号通路的超常激活引起AEBP1的转录上调。AEBP1的上调加速IKBa的降解,从而激活NF-KB。另外,抑制PI3K/AKT-CREB-AEBP1-NF-KB信号通路能够很显著地逆转黑色素瘤细胞对于PLX4032抗性的表型。更为重要的是AEBP1的上调在复发的病例中得到验证。因此,所有的结果揭示了一条新的PI3K/AKT-CREB-AEBP1-NF-KB信号通路,这条信号通路的激活促进了BRAF(V600E)黑色素瘤获得对于BRAF抑制的抗性。说明这条信号通路,特别是AEBP1可以作为一个全新的治疗靶点用于改善或者治疗对于PLX4032具有抗性的黑色素瘤。肿瘤抑制因子p53在细胞受到外界压力刺激的情况下能够被激活,通过启动DNA的修复机制来保护细胞或者在细胞损伤严重不可修复时诱导细胞凋亡以清除损伤细胞,从而达到防止细胞癌变的目的。肿瘤组织中编码p53的基因经常遭到突变,致使其丧失功能,但是在黑色素瘤中野生型p53广泛表达而且表达的水平很高,这与黑色素瘤这种疾病的恶性程度是相悖的,意味着p53在黑色素瘤中丧失了作为一个有效的肿瘤抑制因子的功能。这里我们发现在内质网压力情况下,p53蛋白水平被稳定而上调,主要表现为核内的聚集。在功能上,p53在内质网压力下被激活后,选择性转录上调microRNA149*的宿主基因GPC1,从而上调microRNA149*的表达。P53介导的microRNA149*的上调对于黑色素瘤细胞适应内质网压力是必要的,P53或者其介导的microRNA149*的表达被抑制均显著影响黑色素瘤细胞对于内质网压力的抗性。
[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.
【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：R739.5

【引证文献】