利用VBIM系统探究ZIP在乳腺癌化疗药物耐受中的分子机制

发布时间：2018-08-24 08:03

【摘要】：目前,恶性肿瘤已经成为仅次于心脑血管疾病的人类第二大致死疾病。化疗是目前临床上治疗恶性肿瘤的最重要手段之一,然而由于肿瘤细胞及组织可能会对化疗药物产生耐药,导致患者对该药物治疗不再敏感,最终会引发化疗失败甚至疾病复发。所以肿瘤耐药性的产生是目前化疗药物在临床治疗过程中应用和推广的最主要障碍之一。因此,发现和鉴定肿瘤耐药的相关基因,了解肿瘤细胞和组织的耐药机制,发现全新的药物治疗靶点,有针对性地寻找开发逆转耐药的药物以改进治疗策略等,都已成为化学治疗药物应用研究的热点。我们利用正向遗传学工具对ER阳性乳腺癌常用化疗药物Tamoxifen的耐药基因进行了筛选,并对所发现的ZIP蛋白所导致的耐药机理进行了探究。研究发现,ZIP蛋白可以通过与STAT3的上游蛋白JAK2的启动子区域结合并招募组蛋白去乙酰化酶复合物NURD对该区域进行去乙酰化。这导致JAK2转录水平以及翻译水平表达量的下降。这样,JAK2的下调引起STAT3磷酸化水平的降低并导致其下游蛋白的转录活性的降低,从而在细胞和小鼠体内的这两个水平上对乳腺癌响应Tamoxifen化疗的敏感性进行调控。同时,接受以Tamoxifen作为辅助治疗药物并复发的乳腺肿瘤病人,其成对正常组织与肿瘤组织样本中相关蛋白表达水平与体外实验的结果相一致。以上发现阐明了ZIP蛋白通过作用于JAK2-STAT3通路调控Tamoxifen耐药性的分子机理。可能会为临床上进一步制定针对性的治疗措施或者提供联合用药靶点有着积极的指导意义。
[Abstract]:At present, malignant tumors have become the second leading cause of death after cardiovascular and cerebrovascular diseases. Chemotherapy is one of the most important methods in the treatment of malignant tumors. However, because tumor cells and tissues may become resistant to chemotherapy drugs, patients are no longer sensitive to the drug treatment. Eventually, it can lead to chemotherapy failure and even a relapse. Therefore, the development of tumor resistance is one of the main obstacles to the application and popularization of chemotherapeutic drugs. Therefore, to identify and identify the genes related to drug resistance, to understand the mechanism of drug resistance in tumor cells and tissues, to find new drug therapy targets, and to develop drugs to reverse drug resistance in order to improve treatment strategies, etc. It has become a hot spot in the application of chemotherapeutic drugs. We screened the drug-resistant genes of ER positive breast cancer chemotherapeutic drug Tamoxifen by means of forward genetics, and explored the mechanism of drug resistance caused by ZIP protein. It was found that the STAT3 protein could be deacetylated by binding to the promoter region of the upstream protein JAK2 of STAT3 and recruiting the histone deacetylase complex NURD. This results in a decrease in JAK2 transcription and translation levels. The down-regulation of JAK2 can decrease the phosphorylation level of STAT3 and decrease the transcription activity of its downstream protein, thus regulating the sensitivity of breast cancer to Tamoxifen chemotherapy at both the cellular and mouse levels. At the same time, the expression levels of related proteins in normal tissues and tumor tissues were consistent with the results of in vitro experiments in patients with breast cancer who received Tamoxifen as adjuvant therapy. These findings illustrate the molecular mechanism by which ZIP protein regulates Tamoxifen resistance through its role in the JAK2-STAT3 pathway. It may provide positive guidance for the further development of targeted therapeutic measures or the provision of combined drug targets.
【学位授予单位】：兰州大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R737.9

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