【摘要】：目前,惡性腫瘤已經(jīng)成為僅次于心腦血管疾病的人類(lèi)第二大致死疾病�；熓悄壳芭R床上治療惡性腫瘤的最重要手段之一,然而由于腫瘤細(xì)胞及組織可能會(huì)對(duì)化療藥物產(chǎn)生耐藥,導(dǎo)致患者對(duì)該藥物治療不再敏感,最終會(huì)引發(fā)化療失敗甚至疾病復(fù)發(fā)。所以腫瘤耐藥性的產(chǎn)生是目前化療藥物在臨床治療過(guò)程中應(yīng)用和推廣的最主要障礙之一。因此,發(fā)現(xiàn)和鑒定腫瘤耐藥的相關(guān)基因,了解腫瘤細(xì)胞和組織的耐藥機(jī)制,發(fā)現(xiàn)全新的藥物治療靶點(diǎn),有針對(duì)性地尋找開(kāi)發(fā)逆轉(zhuǎn)耐藥的藥物以改進(jìn)治療策略等,都已成為化學(xué)治療藥物應(yīng)用研究的熱點(diǎn)。我們利用正向遺傳學(xué)工具對(duì)ER陽(yáng)性乳腺癌常用化療藥物Tamoxifen的耐藥基因進(jìn)行了篩選,并對(duì)所發(fā)現(xiàn)的ZIP蛋白所導(dǎo)致的耐藥機(jī)理進(jìn)行了探究。研究發(fā)現(xiàn),ZIP蛋白可以通過(guò)與STAT3的上游蛋白JAK2的啟動(dòng)子區(qū)域結(jié)合并招募組蛋白去乙酰化酶復(fù)合物NURD對(duì)該區(qū)域進(jìn)行去乙�；�。這導(dǎo)致JAK2轉(zhuǎn)錄水平以及翻譯水平表達(dá)量的下降。這樣,JAK2的下調(diào)引起STAT3磷酸化水平的降低并導(dǎo)致其下游蛋白的轉(zhuǎn)錄活性的降低,從而在細(xì)胞和小鼠體內(nèi)的這兩個(gè)水平上對(duì)乳腺癌響應(yīng)Tamoxifen化療的敏感性進(jìn)行調(diào)控。同時(shí),接受以Tamoxifen作為輔助治療藥物并復(fù)發(fā)的乳腺腫瘤病人,其成對(duì)正常組織與腫瘤組織樣本中相關(guān)蛋白表達(dá)水平與體外實(shí)驗(yàn)的結(jié)果相一致。以上發(fā)現(xiàn)闡明了ZIP蛋白通過(guò)作用于JAK2-STAT3通路調(diào)控Tamoxifen耐藥性的分子機(jī)理�？赡軙�(huì)為臨床上進(jìn)一步制定針對(duì)性的治療措施或者提供聯(lián)合用藥靶點(diǎn)有著積極的指導(dǎo)意義。
[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.
【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R737.9

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