支架蛋白Cullins在非小细胞肺癌发生发展中的作用及机制研究

The Cullin family proteins are scaffold proteins for the RING finger type E3 ubiquitin ligases. Our prior published report shows that CUL7 induces epithelial-mesenchymal transition (EMT) in human trophoblast cell lineage. In addition, CUL7 expression downregulats E-cadherin mRNA expression by up-regulating ZEB1 and Slug. Considering the similarity between trophoblast invasion and the invasiveness of tumor cells, we ask an important question of whether CUL7 is also involved in EMT-mediated tumorigensis and metastasis of non-small cell lung cancer (NSCLC). Lung cancer is the leading cause of cancer-related death in both men and women in China. It has been reported that CUL7 mRNA is overexpressed in human NSCLC. Its expression level correlates with poor prognosis. However, the key roles of Cullin family proteins in tumorigenesis and metastasis of lung cancer remain unclear. The purpose of this study is to determine the involvement of Cullin family proteins in carcinogenesis and tumor development. We will first examine the expression of Cullins in NSCLC tissues and cell lines. We will then investigate the roles of CUL1 and CUL7 in NSCLC cell proliferation, apoptosis, invasion and metastasis by using stable overexpression or transient knockdown. Our results may provide pre-clinical evidence that Cullin-RING ligases may serve as new therapeutic targets for NSCLC.

Cullin蛋白家族是Cullin-RING E3泛素连接酶的支架蛋白。我们在滋养层细胞系发现CUL7能引起EMT，CUL7上调ZEB1和Slug，抑制E-cadherin mRNA的表达。鉴于滋养层细胞侵润迁移和肿瘤细胞有许多相似之处，我们提出一个重要问题：CUL7在NSCLC是否参与EMT介导的肿瘤发生和转移。肺癌是中国死亡率最高的恶性肿瘤。研究报道CUL7 mRNA在NSCLC高表达，并与NSCLC病人的预后相关。然而Cullin蛋白家族在肺癌发生转移的作用尚不清楚。本研究目的是确定Cullins在肿瘤发生发展的作用。我们将检测Cullins在NSCLC组织和细胞系的表达，我们将进一步通过CUL1和CUL7稳定过表达或短暂抑制表达，探讨CUL1和CUL7在NSCLC细胞增殖、凋亡、侵袭和转移的作用。我们的结果将为Cullin-RING作为新的NSCLC诊断治疗的靶点提供理论依据。

泛素介导的蛋白质降解途径异常与肿瘤的发生发展密切相关。Cullin-RING E3连接酶是目前已知最大一类泛素连接酶。我们针对Cullin 7（CUL7)在非小细胞肺癌（NSCLC)发生发展中的作用进行了深入研究。首先，采用免疫组织化学法检测组织芯片肺癌及相应癌旁组织中CUL7以及CUL7相关3M复合体基因的表达，发现CUL7的表达与NSCLC的临床分期、淋巴结转移及骨转移正相关。首次发现CUL7通过调控NF-kB通路转录水平调控单核细胞趋化蛋白-1（CCL2)的表达和NSCLC细胞增殖和侵润转移。裸鼠细胞移植瘤形成实验和尾静脉注射模型实验体内研究也发现CUL7促进肿瘤的生长和转移。这些研究结果为了解CUL7基因的功能提供了依据，为进一步阐明Cullin-RING E3连接酶在NSCLC发生发展的作用以及筛选新的诊断治疗靶点提供理论依据。