【摘要】：治療過程中產(chǎn)生的順鉑耐藥現(xiàn)象是影響非小細胞肺癌患者臨床化療的重要因素之一,但其潛在的分子機制尚未完全闡明。本研究旨在發(fā)現(xiàn)與順鉑獲得性耐藥相關(guān)的關(guān)鍵基因及信號通路。基于全轉(zhuǎn)錄組測序技術(shù),我們對非小細胞肺癌A549細胞及相應(yīng)的順鉑耐藥細胞A549/DDP的差異表達基因譜進行了系統(tǒng)分析。轉(zhuǎn)錄組測序共獲得1214個差異表達的基因,其中656個基因在A549/DDP細胞中表達上調(diào),588個基因表達下調(diào)。基于KEGG數(shù)據(jù)庫的數(shù)據(jù)挖掘表明,富集最多差異表達基因的信號通路為PI3K/AKT,MAPK,Focal adhesion 與 Actin cytoskeleton regulation,并且這些通路的關(guān)鍵節(jié)點基因均存在顯著差異表達的情況,表明這些信號通路在調(diào)節(jié)非小細胞肺癌順鉑耐藥方面發(fā)揮著關(guān)鍵的作用。除以上幾大信號通路外,本研究還發(fā)現(xiàn)醛酮還原酶家族l(Aldo-Keto Reductases family 1,AKR1)的三個成員AKR1C1,AKR1C3及AKR1B1同時在A549/DDP細胞中顯著上調(diào),且AKR1C1基因是差異表達最為顯著的基因之一。功能性實驗證實,AKR1C1或AKR1B1酶活抑制劑與順鉑聯(lián)合使用可顯著提高A549/DDP細胞的順鉑敏感性;此外,在A549/DDP細胞中同時敲減AKR1C1和AKR1B1不僅增強了順鉑的細胞毒性,且同時顯著增強了順鉑誘導(dǎo)的細胞凋亡作用。以上結(jié)果表明,AKR1家族中的AKR1C1和AKR1B1基因在調(diào)節(jié)A549細胞順鉑耐藥中起到了關(guān)鍵的作用。本研究為非小細胞肺癌臨床治療提供了新的分子靶標,在臨床樣本中驗證本研究發(fā)現(xiàn)的分子靶標將是我們下一步工作的重點。
[Abstract]:Cisplatin resistance is one of the important factors affecting the clinical chemotherapy of patients with non-small cell lung cancer, but its potential molecular mechanism has not been fully elucidated. This study aims to identify key genes and signaling pathways associated with cisplatin acquired resistance. Based on the whole transcriptome sequencing technique, we systematically analyzed the differentially expressed gene profiles of A549/DDP in A549 cells and cisplatin resistant cells of non-small cell lung cancer (NSCLC). A total of 1214 differentially expressed genes were obtained by transcriptome sequencing, of which 656 genes were up-regulated and down-regulated in A549/DDP cells. Data mining based on KEGG database showed that the signal pathways that enriched the most differentially expressed genes were PI3K / AKTK-MAPKFocal adhesion and Actin cytoskeleton regulation, and the key node genes of these pathways were significantly differentially expressed. These signaling pathways play a key role in regulating cisplatin resistance in non-small cell lung cancer. In addition to these major signal pathways, we also found that AKR1C1AK-R1C3 and AKR1B1, three members of the aldehyde-ketone reductase family (Aldo-Keto Reductases family 1), were up-regulated in A549/DDP cells at the same time, and AKR1C1 gene was one of the most significant differentially expressed genes. Functional experiments showed that the combination of AKR1C1 or AKR1B1 enzyme inhibitor with cisplatin could significantly increase the cisplatin sensitivity of A549/DDP cells, in addition, knockout of AKR1C1 and AKR1B1 in A549/DDP cells not only enhanced the cytotoxicity of cisplatin, but also increased the cytotoxicity of cisplatin. At the same time, the apoptosis induced by cisplatin was significantly enhanced. These results suggest that the AKR1C1 and AKR1B1 genes in the AKR1 family play a key role in regulating cisplatin resistance in A549 cells. This study provides a new molecular target for the clinical treatment of non-small cell lung cancer (NSCLC).
【學位授予單位】：西北大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R734.2

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1 Valentina Grossi;Alessia Peserico;Tugsan Tezil;Cristiano Simone;;p38α MAPK pathway:A key factor in colorectal cancer therapy and chemoresistance[J];World Journal of Gastroenterology;2014年29期

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本文編號：2165352