【作者】 马秀梅；

【导师】 左连富；

【作者基本信息】 河北医科大学 ， 病理学与病理生理学， 2006， 博士

【摘要】 目的:胃癌是消化道最常见的高度恶性肿瘤,其预后差,治疗难度大,死亡率高。因此,探讨胃癌的发病机制,寻找新的预防和治疗靶点以及有效的治疗药物,对降低胃癌发病率和死亡率,提高生存率和延长患者的寿命,将有十分重要的意义。S期激酶相关蛋白2(S-phase kinase-associated protein 2,Skp2)促进泛素介导的细胞周期素依赖激酶抑制剂p27蛋白降解,是细胞由G1期进入S期所必需。研究发现,Skp2过表达参与细胞转化和肿瘤形成,肿瘤抑制蛋白PTEN通过调节Skp2调节泛素依赖的p27的降解。Skp2可能是一些抑制细胞周期的抗肿瘤药物的新靶点。乙酰肝素酶(Heparanase,HPA)是目前发现的哺乳动物细胞中唯一能切割细胞外基质和基底膜中硫酸乙酰肝素的内源性糖苷酶。HPA在炎症、血管生成、肿瘤侵袭和转移等过程中起决定性的作用,被认为是抗肿瘤治疗的新靶点。核转录因子κB(NF-κB)是二聚体转录因子,参与调解炎症和凋亡有关基因的表达。最近研究表明,NF-κB也是基质金属蛋白酶-9(MMP-9)和尿激酶型纤溶酶原激活剂(uPA)的转录因子,与肿瘤转移有关,最近体外研究还表明,NF-κB也调节HPA的表达。过氧化物酶体增殖物激活受体γ(Peroxisome proliferators-activated receptorγ,PPARγ)属核激素受体超家族的成员,在介导脂肪细胞分化和调节脂肪代谢中起重要作用,参与动脉粥样硬化、炎症、肥胖、糖尿病、免疫反应和衰老等的病理生理过程。最近研究表明,PPARγ除了这些经典作用以外,也与肿瘤形成有关,PPARγ的天然配体和合成配体在一些肿瘤有抗肿瘤的作用。但也有研究显示,PPARγ的配体对肿瘤细胞生长的影响具有与浓度有关的双重作用,低浓度促进生长,高浓度抑制生长。最近,PPARγ的选择性和不可逆性拮抗剂GW9662也被鉴定。RNA干扰(RNA interference, RNAi)是由双链RNA(double-stranded RNAs, dsRNA )分子介导的序列特异性转录后基因沉默( post-更多还原

【Abstract】 Objectives: Gastric carcinoma is one of the most common malignant tumors. Its prognosis is poor, therapy is very difficult and mortality is enormous high. Therefore, it is extremely important to investigate pathogenesis and search new target of prevention and therapy and effective drug in gastric carcinoma for decreased morbidity and mortality, increased survival rate and prolonged life span of gastric carcinoma patients.S-phase kinase-associated protein 2 (Skp2) is a positive regulator of G1-S transition and promotes ubiquitin-mediated proteolysis of the cyclin- dependent kinase inhibitor p27. Some research have shown that Skp2 overexpression has been implicated in cell transformation and oncogenesis, and tumor suppressor protein PTEN may regulate ubiquitin-mediated p27 proteolysis through regulating Skp2. Skp2 may provide a new target for anticancer therapy drugs inhibiting cell cycle proceeding.Heparanase (HPA) is the only endoglycosidase in mammal cell so far that degrades heparan sulfate in extracellular matrix and basement membrane. HPA plays a central role in inflammation, angiogenesis and invasiveness and metastasis of diverse malignant tumors. Perhaps it is a new target for anticancer therapy. NF-κB is a dimeric transcription factor that is involved in the regulation of genes associated with inflammation and apoptosis. Recent studies have shown that NF-κB is also a transcriptional factor of matrix metalloproteinases 9 (MMP9) and urokinase plasminogen activator (uPA) and plays a role in the metastatic process of malignant tumor. Recent studies in vitro have shown that NF-κB also regulated HPA expression.Peroxisome proliferators-activated receptorγ(PPARγ) that belongs to the更多还原