靶向siRNA阻断NF-κB信号通路对胆管癌增殖和侵袭影响实验研究
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摘要
胆管癌早期诊断困难以及其自身临床病理特征,癌细胞容易沿血管及神经鞘浸润扩散,手术虽然是唯一可能获得治愈的手段,但大部分根治手术切除率低术后易复发,且放化疗无助于生存率的提高,寻找确切有效的胆管癌治疗手段具有重要的现实意义。胆管癌发病的高危因素共同病理特征是胆道的慢性炎症。NF-κB作为“炎癌链”的关键调控环节,在多种肿瘤细胞的增殖侵袭调控中发挥中枢性作用,为此本研究以NF-κBp65为潜在的抗肿瘤靶点且进行干预研究,以期阻断胆管癌发生发展进程,达到化学预防和治疗目的。以免疫组化及western blot法检测临床胆管癌石蜡及新鲜标本的NF-κBp65分布表达发现:肿瘤分级程度越低,侵袭性越明显,越伴有淋巴转移,NF-κBp65越趋向细胞核分布,COX-2及iNOS亦表达并与NF-κBp65呈现明显相关性。据此以NF-κBp65为靶点,T7RNA聚合酶体外转录体系设计合成三个靶向siRNA,以RT-PCR、western blot验证三个靶位点对NF-κBp65基因mRNA干扰效果均有效,应用其中之一靶位点siRNA体体内外验证阻断NF-κBp65表达对胆管癌影响效果并探讨了抗肿瘤可能机制。本文包括五部分内容:胆管癌组织中NF-κB表达与COX-2及iNOS蛋白表达的相关性;体外转录合成NF-κBp65靶向siRNA的构建及功能筛选;NF-κBp65靶向siRNA体外抑制胆管癌细胞研究;靶向NF-κB小干扰RNA抑制胆管癌细胞下游COX-2、iNOS基因表达作用;靶向NF-κB的siRNA对胆管癌裸鼠移植瘤影响作用。
Surgical resection offers the only chance to cure not only for its difficult of diagnosis but also itself clinical pathological characteristics with infiltration and spread out along the vessel and the nerve sheath. However, the outcome of patients with advanced cholangiocarcinoma still remains the higher rate of tumor recurrence and extremely poor even after resection. Radiotherapy and chemotherapy does not improve survival rate. For the sake of these, it is practical importance to study the precise and effective treatment of cholangiocarcinoma. Epidemiological investigation of risk factors for cholangiocarcinoma is common pathological features of chronic inflammation. NF-κB as a ubiquitous transcription factor, activation abnormal in a variety of tumor cell proliferation and invasive regulation play important of role, is "inflammation-associated carcinoma chain "of key control aspect. The topic is precisely based on this issue cholangiocarcinoma of the main pathological features of chronic inflammation, focus on NF-κB signaling pathway,‘inflammation-associat -ed carcinoma chain’the key aspect of regulation, observating the cholangiocarcinoma NF-κB signal expression through the experiments in vivo and in vitro ,and use of NF-κBp65 targeting small interfering technology to block NF-κB signaling pathway to explore the role of anti-proliferation and invasiveness in vivo and in vitro.This paper included 5 sections.
Surgical resection offers the only chance to cure not only for its difficult of diagnosis but also itself clinical pathological characteristics with infiltration and spread out along the vessel and the nerve sheath. However, the outcome of patients with advanced cholangiocarcinoma still remains the higher rate of tumor recurrence and extremely poor even after resection. Radiotherapy and chemotherapy does not improve survival rate. For the sake of these, it is practical importance to study the precise and effective treatment of cholangiocarcinoma. Epidemiological investigation of risk factors for cholangiocarcinoma is common pathological features of chronic inflammation. NF-κB as a ubiquitous transcription factor, activation abnormal in a variety of tumor cell proliferation and invasive regulation play important of role, is "inflammation-associated carcinoma chain "of key control aspect. The topic is precisely based on this issue cholangiocarcinoma of the main pathological features of chronic inflammation, focus on NF-κB signaling pathway,‘inflammation-associat -ed carcinoma chain’the key aspect of regulation, observating the cholangiocarcinoma NF-κB signal expression through the experiments in vivo and in vitro ,and use of NF-κBp65 targeting small interfering technology to block NF-κB signaling pathway to explore the role of anti-proliferation and invasiveness in vivo and in vitro.This paper included 5 sections.
引文
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