本文關(guān)鍵詞： TOPK 肺癌 EGFR-TKIs耐藥 c-Jun AP-1　出處：《第四軍醫(yī)大學(xué)》2015年碩士論文　論文類型：學(xué)位論文

【摘要】：肺癌是嚴(yán)重威脅人類生命健康的重大疾病,也是全球癌癥相關(guān)性死亡的首要原因,其中NSCLC約占85%。當(dāng)前,表皮生長(zhǎng)因子受體-酪氨酸激酶抑制劑(EGFR-TKIs)在NSCLC治療方面獲得了巨大的成功,已發(fā)展成為肺癌治療的一線藥物。盡管如此,臨床中大部分EGFR突變陽性患者經(jīng)過一段時(shí)間的治療后對(duì)EGFR-TKIs產(chǎn)生繼發(fā)性耐藥,因此對(duì)EGFR-TKIs獲得性耐藥機(jī)制及其臨床應(yīng)對(duì)策略的研究成為靶向治療領(lǐng)域的又一研究熱點(diǎn)�，F(xiàn)有研究表明,非小細(xì)胞肺癌EGFR-TKIs獲得性耐藥機(jī)制主要表現(xiàn)為細(xì)胞繞過EGFR直接通過其下游分子來激活肺癌細(xì)胞生長(zhǎng)的信號(hào)通路。因此,越來越多的研究者開始關(guān)注EGFR信號(hào)通路的下游分子以及與肺癌生長(zhǎng)密切相關(guān)的一些蛋白激酶,以克服EGFR-TKIs的耐藥問題。TOPK是一種由322個(gè)氨基酸構(gòu)成的絲氨酸-蘇氨酸蛋白激酶,首次發(fā)現(xiàn)于淋巴因子激活的殺傷性T細(xì)胞。以往研究表明,TOPK與有絲分裂期間紡錘體的功能密切相關(guān),TOPK的敲除將導(dǎo)致細(xì)胞胞質(zhì)分裂的推遲。近年來的研究發(fā)現(xiàn),TOPK在多種腫瘤細(xì)胞中呈強(qiáng)表達(dá),與腫瘤的發(fā)生發(fā)展密切相關(guān)。TOPK與細(xì)胞內(nèi)多個(gè)凋亡相關(guān)蛋白的活化和表達(dá)有關(guān),參與調(diào)控細(xì)胞的凋亡。已有研究發(fā)現(xiàn),穩(wěn)定干涉TOPK表達(dá)后,可以對(duì)細(xì)胞內(nèi)的一些凋亡相關(guān)蛋白以及細(xì)胞周期蛋白的表達(dá)水平產(chǎn)生不同程度的影響,提示TOPK可能在癌癥耐藥過程中具有重要的作用。AP-1是一個(gè)二聚體的轉(zhuǎn)錄因子,包含可以與DNA結(jié)合的亮氨酸拉鏈結(jié)構(gòu)域。Jun(c-Jun,Jun B和Jun D)和Fos(Fos,Fos B,Fra-1,Fra2)亞家族是主要的AP-1蛋白�，F(xiàn)有證據(jù)表明,AP-1在腫瘤細(xì)胞的增殖、轉(zhuǎn)化等方面發(fā)揮了重要作用。c-Jun是癌基因,c-Jun活化后可以調(diào)節(jié)靶基因轉(zhuǎn)錄,從而參與細(xì)胞的生長(zhǎng)、分化和凋亡等多種生理過程。c-Jun的調(diào)節(jié)與AP-1的轉(zhuǎn)錄活性密切相關(guān)。但c-Jun已知最主要的調(diào)節(jié)蛋白是JNK(c-Jun amino-terminal kinase,c-Jun氨基末端激酶)。JNK是絲裂原激活的蛋白激酶超家族成員,JNK接受上游信號(hào)后被激活,從而與c-Jun結(jié)合并且磷酸化2個(gè)絲氨酸/蘇氨酸叢,Ser63/73和Thr91/93,進(jìn)而激活c-Jun增強(qiáng)其轉(zhuǎn)錄活性。c-Jun磷酸化后轉(zhuǎn)錄活性增強(qiáng),蛋白的半衰期顯著延長(zhǎng)。但是JNK只在各種應(yīng)激狀態(tài)下被激活,其中最有效的方式是導(dǎo)致DNA損傷的UV刺激。然而在腫瘤正常生長(zhǎng)狀態(tài)下不存在UV刺激,JNK的活化水平較低,那么尋找肺癌細(xì)胞中新的能夠活化c-Jun進(jìn)而調(diào)節(jié)AP-1轉(zhuǎn)錄活性的蛋白激酶是肺癌研究的關(guān)鍵。眾所周知,肺癌細(xì)胞能夠大量自分泌EGF,促進(jìn)腫瘤細(xì)胞的生長(zhǎng)。腫瘤細(xì)胞在EGF刺激下不能活化JNK,但可以活化TOPK,并呈劑量依賴性,這就使得EGFR-TKIs耐藥肺癌細(xì)胞通過TOPK-c-Jun-AP-1通路促進(jìn)腫瘤細(xì)胞生長(zhǎng)成為可能�！灸康摹竣俅_立TOPK在EGFR-TKIs耐藥肺癌細(xì)胞生長(zhǎng)中的重要作用;②闡明TOPK通過磷酸化c-Jun進(jìn)而促進(jìn)AP-1轉(zhuǎn)錄活性的具體分子機(jī)制�！痉椒ê徒Y(jié)果】①首先采用組織芯片技術(shù)和western blot方法分別在肺癌患者組織和肺癌細(xì)胞系中檢測(cè)了TOPK的表達(dá)情況。結(jié)果發(fā)現(xiàn)在EGFR-TKIs耐藥的肺癌患者和肺癌細(xì)胞株中都存在TOPK高表達(dá)現(xiàn)象。接下來采用慢病毒干涉技術(shù)建立了A549 sh MOCK和A549 sh TOPK穩(wěn)轉(zhuǎn)細(xì)胞系,進(jìn)一步利用CCK8技術(shù)和軟瓊脂克隆形成實(shí)驗(yàn)觀察干涉TOPK表達(dá)對(duì)A549 sh MOCK和A549 sh TOPK細(xì)胞生長(zhǎng)以及對(duì)吉非替尼敏感性的影響。結(jié)果發(fā)現(xiàn)在EGFR-TKIs耐藥的A549細(xì)胞中下調(diào)TOPK的表達(dá)可以明顯抑制它的增殖和克隆形成能力,并且顯著提高它對(duì)于吉非替尼的敏感性。而在吉非替尼敏感的肺癌細(xì)胞株H358中提高TOPK的表達(dá)后,該細(xì)胞對(duì)吉非替尼的敏感性下降。②采用western blot方法檢測(cè)了EGFR-TKIs耐藥肺癌細(xì)胞A549和敏感肺癌細(xì)胞H358中TOPK及相關(guān)底物的蛋白表達(dá)水平,結(jié)果發(fā)現(xiàn),TOPK活化水平與c-Jun磷酸化表達(dá)水平呈正相關(guān)。進(jìn)一步采用同源建模預(yù)測(cè)發(fā)現(xiàn)TOPK可以和c-Jun相互結(jié)合。③通過哺乳動(dòng)物雙雜交系統(tǒng)證明了TOPK與c-Jun存在相互作用。采用免疫共沉淀方法分別在外源性表達(dá)TOPK和c-Jun的HEK293細(xì)胞和內(nèi)源性表達(dá)的A549細(xì)胞中證實(shí)了TOPK與c-Jun存在相互作用。進(jìn)一步利用體外激酶技術(shù)發(fā)現(xiàn)TOPK對(duì)c-Jun全長(zhǎng)蛋白具有磷酸化作用。并且通過點(diǎn)突變分析證明TOPK磷酸化c-Jun的氨基酸位點(diǎn)為Ser63和Ser73。且利用一系列western blot實(shí)驗(yàn)證實(shí)了TOPK對(duì)c-Jun的磷酸化作用。④采用AP-1 luciferase報(bào)告質(zhì)粒技術(shù),觀察TOPK磷酸化c-Jun對(duì)AP-1轉(zhuǎn)錄活性的影響,結(jié)果發(fā)現(xiàn)TOPK磷酸化c-Jun可以顯著提高AP-1的轉(zhuǎn)錄活性。并采用real time PCR和western blot技術(shù)檢測(cè)AP-1靶基因CCND1和CDC2 m RNA水平和蛋白水平的表達(dá),結(jié)果發(fā)現(xiàn)TOPK的表達(dá)水平與CCND1和CDC2 m RNA和蛋白的表達(dá)水平呈正相關(guān)。⑤采用裸鼠移植瘤模型,觀察在體內(nèi)TOPK表達(dá)對(duì)肺癌細(xì)胞A549吉非替尼耐藥性的影響,結(jié)果發(fā)現(xiàn)A549 sh TOPK組腫瘤生長(zhǎng)速度明顯低于A549 sh MOCK組,并且A549 sh TOPK組對(duì)吉非替尼的敏感性顯著高于A549 sh MOCK組。并利用western blot方法檢測(cè)各組移植瘤中TOPK、c-Jun及其磷酸化蛋白的表達(dá)水平,結(jié)果發(fā)現(xiàn)下調(diào)TOPK的表達(dá)能夠明顯降低c-Jun的磷酸化水平�！窘Y(jié)論】通過本課題的研究,我們發(fā)現(xiàn)了TOPK在EGFR-TKIs耐藥肺癌細(xì)胞生長(zhǎng)中發(fā)揮了重要作用,并闡明了其作用機(jī)制。首先,我們發(fā)現(xiàn)TOPK在EGFR-TKIs耐藥肺癌細(xì)胞中高表達(dá),能促進(jìn)肺癌細(xì)胞的生長(zhǎng),并與肺癌細(xì)胞EGFR-TKIs耐藥性相關(guān);其次,發(fā)現(xiàn)TOPK與c-Jun存在相互作用,TOPK通過磷酸化c-Jun第63、73位絲氨酸而活化c-Jun;最后,我們發(fā)現(xiàn)TOPK活化c-Jun可以提高轉(zhuǎn)錄因子AP-1的轉(zhuǎn)錄活性,進(jìn)而促進(jìn)AP-1靶基因CCND1和CDC2的表達(dá)水平,從而闡明了TOPK通過磷酸化c-Jun提高AP-1轉(zhuǎn)錄活性,促進(jìn)EGFR-TKIs耐藥肺癌細(xì)胞生長(zhǎng)的具體分子機(jī)制,為肺癌的生物學(xué)治療提供了TOPK這一新的靶分子,為肺癌個(gè)體化治療的實(shí)施提供了一種新的可能性。
[Abstract]:Lung cancer is a serious threat to the life and health of human beings, is the world's leading cause of cancer-related death, which accounts for about NSCLC 85%. at present, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) has achieved great success in the treatment of NSCLC, the development has become the first-line drug in the treatment of lung cancer. However, the mutation positive patients after a period of time after treatment of EGFR-TKIs secondary resistance to most of the EGFR clinic, therefore become a research hotspot to target treatment in the field of research strategy resistance mechanism and clinical response to EGFR-TKIs. The existing research shows that non small cell lung cancer EGFR-TKIs acquired resistance mechanism mainly for cells to bypass the EGFR directly through the the downstream molecules to activate the signal pathway of lung cancer cell growth. Therefore, more and more researchers begin to pay attention to the EGFR signaling pathway Travel and the growth of some protein kinase molecules closely related with lung cancer, in order to overcome the problem of.TOPK resistance of EGFR-TKIs is composed of a 322 amino acid serine threonine protein kinase, first discovered in lymphokine activated killer T cells. Previous studies showed that TOPK and mitotic spindle during the function is closely related to TOPK the knockout will lead to delayed cytokinesis. Recent studies have found that TOPK was highly expressed in tumor cells, and tumor development is closely related to the activation of.TOPK cells with multiple apoptosis related proteins and expression of apoptosis is involved in the regulation of cells. It has been found that stable expression of TOPK interference that can produce different effects on the cells of some apoptosis related proteins and cell cycle protein expression levels, suggesting that TOPK may have in the process of cancer drug resistance .AP-1 is an important transcription factor two dimers, contains a leucine zipper domain.Jun can be combined with DNA (c-Jun, Jun B and Jun D) and Fos (Fos, Fos, B, Fra-1, Fra2) is a major subfamily of AP-1 protein. The available evidence suggests that AP-1 in the proliferation of tumor cells the transformation has played an important role in.C-Jun is an oncogene, c-Jun activation can regulate the transcription of target genes, which are involved in cell growth, differentiation and apoptosis of a variety of physiological processes, the regulation of.C-Jun and AP-1 transcriptional activity are closely related. But c-Jun is known the main regulatory protein is JNK (c-Jun amino-terminal kinase, c-Jun N terminal kinase).JNK is a member of the superfamily of mitogen activated protein kinase, JNK accept upstream signals after being activated, which combined with c-Jun and phosphorylation of 2 serine / threonine Ser63/73 cluster, and Thr91/93, which can activate c-Jun to enhance its transcription Enhance the transcriptional activity of activated.C-Jun phosphorylation, protein half-life was prolonged. But JNK only in various stress conditions is activated, which is the most effective way to cause DNA damage. However, the stimulation of UV in tumor normal growth does not exist under UV stimulation, the activation of JNK is low, so to find the activation of c-Jun and the new regulation of AP-1 transcriptional activity in lung cancer cells is the key protein kinase in lung cancer research. As everyone knows, a large number of lung cancer cells to autocrine EGF, promote the growth of tumor cells. Tumor cell activation of JNK under the stimulation of EGF can not, but can activate TOPK, in a dose dependent manner, which makes EGFR-TKIs drug resistant lung cancer cells promote tumor cell the growth is possible through the TOPK-c-Jun-AP-1 pathway. [Objective] to establish the important role of TOPK in the growth of EGFR-TKIs drug resistance in lung cancer cells; the elucidation of TOPK phosphorylation by c-Ju N and promote the molecular mechanism of the transcriptional activity of AP-1. [results] the first method and by using tissue chip technique and Western blot method. The expression of TOPK were detected in patients with lung cancer and lung cancer cell lines. The results showed that high expression of TOPK exist in EGFR-TKIs resistant patients with lung cancer and lung cancer cell lines. The next A549 sh MOCK interference technology was established and the A549 sh TOPK cell lines stably transfected by lentivirus, further use of CCK8 technology and soft agar experimental observation on the expression of A549 sh interference TOPK MOCK and A549 sh TOPK on cell growth and the effects of gefitinib sensitivity. The results showed that the expression of TOPK in EGFR-TKIs resistant A549 cells can significantly inhibit the proliferation and clone its formation ability, and improve it to gefitinib sensitivity. In gefitinib sensitive lung cancer To improve the expression of TOPK in H358 cells, the cells to gefitinib decreased imatinib sensitivity. Using Western blot method to detect TOPK EGFR-TKIs drug resistant lung cancer cells A549 and sensitive lung cancer H358 cells and related substrate protein expression level, results showed that the activation of TOPK and phosphorylation of c-Jun expression level was positively related to further. Using homology modeling prediction of interaction between TOPK and c-Jun can be found. Through the mammalian two hybrid system proved that the interaction between TOPK and c-Jun. The HEK293 cells and endogenous CO immunoprecipitation method the expression of TOPK and c-Jun respectively. The expression of exogenous A549 cells confirmed the interaction between TOPK and c-Jun. Further by in vitro kinase technology TOPK has found that phosphorylation of c-Jun full-length protein. And through the point mutation analysis demonstrated that amino acid sites of phosphorylation of TOPK c-Jun Ser63 And Ser73. and blot western by using a series of experiments confirmed that phosphorylation of TOPK c-Jun. The AP-1 luciferase reporter plasmid technology, to observe the effect of TOPK phosphorylation on the transcriptional activity of AP-1 c-Jun, it was found that TOPK phosphorylation of c-Jun can significantly improve the transcriptional activity of AP-1. And the expression of real time PCR and Western blot detection technology AP-1 CCND1 and CDC2 m RNA of target gene and protein level, the expression level of TOPK and CCND1 CDC2 and m RNA and protein expression levels were positively correlated. Applying the nude mice model in vivo, to observe the expression of TOPK on lung cancer cell A549 Kyrgyzstan effect for developed resistance, the results showed that A549 sh TOPK group the tumor growth rate was significantly lower than that of A549 SH and A549 sh MOCK group, TOPK group of gefitinib sensitivity was significantly higher than that of A549 SH and Western MOCK group. Using blot method to detect the transplantation In TOPK, the expression level of c-Jun protein and its phosphorylation, found that down-regulation of TOPK expression significantly decreased the phosphorylation of c-Jun. [Conclusion] through this study, we found that TOPK play an important role in the growth of EGFR-TKIs drug resistant lung cancer cells, and to clarify its mechanism. Firstly, we found that the high expression of TOPK EGFR-TKIs in drug resistant lung cancer cells, can promote the growth of lung cancer cells, and EGFR-TKIs lung cancer cell drug resistance; secondly, found the interaction between TOPK and c-Jun, TOPK by phosphorylation of c-Jun at serine 63,73 and activation of c-Jun; finally, we found that the activation of TOPK c-Jun can enhance the transcription activity of AP-1. And then promote the expression of AP-1 target genes CCND1 and CDC2, which explained the TOPK increased AP-1 transcriptional activity by phosphorylation of c-Jun, promote the growth of lung cancer cells resistant to EGFR-TKIs The specific molecular mechanism provides a new target TOPK for the biological treatment of lung cancer, which provides a new possibility for the implementation of individualized treatment of lung cancer.

【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：R734.2

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