吲哚美辛对结肠癌细胞成瘤裸鼠作用的蛋白质组学研究
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摘要
研究背景
结肠癌是常见的消化道肿瘤，确诊时多属中晚期，手术效果较差，寻找有效防治结肠癌的药物一直是人们关注的热点。随着对慢性炎症与肿瘤发生发展之间关系研究的深入，非甾体类抗炎药(NSAIDs)抗结肠癌的作用备受重视。大量资料显示长期服用NSAIDs可降低结肠癌的发病率，多种NSAIDs可通过抑制细胞增殖、诱导细胞凋亡等产生抗肿瘤作用，吲哚美辛(indomethacin，IN)也是研究较多的此类药物之一，但具体的分子生物学机制未完全明确。NSAIDs的抗炎活性主要通过环氧合酶2(COX-2)实现，COX-2在结肠腺瘤和结肠腺癌中表达增高，COX-2抑制剂可抑制肿瘤增长，因此环氧合酶2被认为在此过程中起关键作用。但COX-2并不能解释NSAIDs抗肿瘤的全部，因为NSAIDs对不表达COX的癌细胞同样可产生抗肿瘤效应，不具有环氧合酶抑制活性的NSAIDs衍生物也有抗肿瘤作用，提示除环氧合酶外，NSAIDs还有其他作用靶点存在。现有研究表明NSAIDs可通过PPARγ、PPARδ和RKS2等非COX依赖性途径发挥抗肿瘤作用。由于大肠癌的发生是一多因素多步骤的过程，涉及多个基因的突变，而NSAIDs抗结肠癌的作用涉及到大肠癌发生发展的多个环节，具体作用机制较为复杂，故常规方法很难做到全面的研究。蛋白质组学是动态研究一个细胞、组织或有机体中所表达全部蛋白质的新兴学科，利用蛋白质组学研究的高通量特点，有望发现药物具体作用机制的线索及新的药物靶标。我们先前的研究已发现吲哚美辛可明显抑制结肠癌细胞成瘤裸鼠瘤组织的生长，为此我们利用不表达COX-2的HCT116结肠癌细胞接种至裸鼠皮下，以成瘤裸鼠作研究对象，用蛋白质组学技术对吲哚美辛抗结肠癌的分子机制进行深入研究。
第一部分：吲哚美辛对结肠癌细胞裸鼠成瘤组织作用的功能蛋白质组学分析
目的：建立吲哚美辛处理组与未处理组结肠癌HCT116细胞裸鼠成瘤组织的双向凝胶电泳图谱，分析两组间差异表达蛋白质点；方法：
Background:
Colorectal cancer is among the leading causes of cancer-related mortality, most patients were diagnosed in late stage, and the effects of operation on them were poor. Thus searching for effective drugs to the therapy, or those with potential to prevent colorectal cancer, is of great importance. Followed by the further understanding of relationship between chronic inflammation and tumor progression, nonsteroidal anti-inflammatory drugs (NSAIDs), as the main anti-inflammation drugs, draw more and more research attention for their functions of cancer therapy and chemoprevention. Ample data show that regular intake of NSAIDs is associated with decreased incidence of colorectal adenoma or colorectal cancer. NSAIDs have shown effects on tumor in many sites of the body through anti-proliferation and inducing apoptosis. Indomethacin has been frequently used to study the effect on colorectal cancer as well as cancers in other sites. Despite lots of researches related to NSAIDs including indomethacin's effect on CRC, concrete mechanism of its anti-tumor activity is not completely known. Because cyclooxygenase-2 (COX-2) is the main target through which NSAIDs exert their anti-inflammation effect, colorectal adenoma and adenocarcinoma have a high level expression of COX-2, and COX-2 specific inhibiting drugs such as celecoxib can impede cancer proliferation, so COX-2 has been thought to play a pivotal role in this process. However, COX-2 could not explain all the mechanism of NSAIDs' anti-cancer effects, other evidences exhibited that COX-independent cancer-chemotherapy mechanisms of NSAIDs still exist, since NSAIDs had antiproliferative effects on cell lines which do not expressed COX, anf derivations of NSAIDs which do not inhibit COX also have antitumor effects. Several studies have demonstrated that NSAIDs including indomethcin can play a chemopreventive and therapeutic activity through targets such as ribosomal S6 kinase 2 (RSK2), peroxisome proliferator-activated receptor
结肠癌是常见的消化道肿瘤，确诊时多属中晚期，手术效果较差，寻找有效防治结肠癌的药物一直是人们关注的热点。随着对慢性炎症与肿瘤发生发展之间关系研究的深入，非甾体类抗炎药(NSAIDs)抗结肠癌的作用备受重视。大量资料显示长期服用NSAIDs可降低结肠癌的发病率，多种NSAIDs可通过抑制细胞增殖、诱导细胞凋亡等产生抗肿瘤作用，吲哚美辛(indomethacin，IN)也是研究较多的此类药物之一，但具体的分子生物学机制未完全明确。NSAIDs的抗炎活性主要通过环氧合酶2(COX-2)实现，COX-2在结肠腺瘤和结肠腺癌中表达增高，COX-2抑制剂可抑制肿瘤增长，因此环氧合酶2被认为在此过程中起关键作用。但COX-2并不能解释NSAIDs抗肿瘤的全部，因为NSAIDs对不表达COX的癌细胞同样可产生抗肿瘤效应，不具有环氧合酶抑制活性的NSAIDs衍生物也有抗肿瘤作用，提示除环氧合酶外，NSAIDs还有其他作用靶点存在。现有研究表明NSAIDs可通过PPARγ、PPARδ和RKS2等非COX依赖性途径发挥抗肿瘤作用。由于大肠癌的发生是一多因素多步骤的过程，涉及多个基因的突变，而NSAIDs抗结肠癌的作用涉及到大肠癌发生发展的多个环节，具体作用机制较为复杂，故常规方法很难做到全面的研究。蛋白质组学是动态研究一个细胞、组织或有机体中所表达全部蛋白质的新兴学科，利用蛋白质组学研究的高通量特点，有望发现药物具体作用机制的线索及新的药物靶标。我们先前的研究已发现吲哚美辛可明显抑制结肠癌细胞成瘤裸鼠瘤组织的生长，为此我们利用不表达COX-2的HCT116结肠癌细胞接种至裸鼠皮下，以成瘤裸鼠作研究对象，用蛋白质组学技术对吲哚美辛抗结肠癌的分子机制进行深入研究。
第一部分：吲哚美辛对结肠癌细胞裸鼠成瘤组织作用的功能蛋白质组学分析
目的：建立吲哚美辛处理组与未处理组结肠癌HCT116细胞裸鼠成瘤组织的双向凝胶电泳图谱，分析两组间差异表达蛋白质点；方法：
Background:
Colorectal cancer is among the leading causes of cancer-related mortality, most patients were diagnosed in late stage, and the effects of operation on them were poor. Thus searching for effective drugs to the therapy, or those with potential to prevent colorectal cancer, is of great importance. Followed by the further understanding of relationship between chronic inflammation and tumor progression, nonsteroidal anti-inflammatory drugs (NSAIDs), as the main anti-inflammation drugs, draw more and more research attention for their functions of cancer therapy and chemoprevention. Ample data show that regular intake of NSAIDs is associated with decreased incidence of colorectal adenoma or colorectal cancer. NSAIDs have shown effects on tumor in many sites of the body through anti-proliferation and inducing apoptosis. Indomethacin has been frequently used to study the effect on colorectal cancer as well as cancers in other sites. Despite lots of researches related to NSAIDs including indomethacin's effect on CRC, concrete mechanism of its anti-tumor activity is not completely known. Because cyclooxygenase-2 (COX-2) is the main target through which NSAIDs exert their anti-inflammation effect, colorectal adenoma and adenocarcinoma have a high level expression of COX-2, and COX-2 specific inhibiting drugs such as celecoxib can impede cancer proliferation, so COX-2 has been thought to play a pivotal role in this process. However, COX-2 could not explain all the mechanism of NSAIDs' anti-cancer effects, other evidences exhibited that COX-independent cancer-chemotherapy mechanisms of NSAIDs still exist, since NSAIDs had antiproliferative effects on cell lines which do not expressed COX, anf derivations of NSAIDs which do not inhibit COX also have antitumor effects. Several studies have demonstrated that NSAIDs including indomethcin can play a chemopreventive and therapeutic activity through targets such as ribosomal S6 kinase 2 (RSK2), peroxisome proliferator-activated receptor
引文
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