MPS-1通过整合素β4调控胃癌细胞转移的作用及机制研究

Metastasis is one of the major causes of lethality in gastric patients. Metallopanstimulin-1(MPS-1) is one of the genes that we discovered correlated with gastric cancer by SEREX analysis. Our previous studies found that MPS-1 had a close relationship with the generation and metastasis of gastric cancer. cDNA microarray analysis revealed that metastasis related gene integrin β4 (ITGB4) may be one of the key downstream genes of MPS-1,which mediates the function of MPS-1 in the metastasis of gastric cancer. This project focus on exploring the role of MPS-1 in regulating gastric cancer cells metastasis and disclose possible mechanisms. Firstly, we will investigate the role of MPS-1 in regulating metastasis of gastric cancer cells. By upregulating and downregulating the expression of MPS-1, we will validate the effects of MPS-1 in regulating gastric cancer cells metastatic capacity through in vitro migration/invasion asssays and in vivo metastasis models. Secondly, based on the relativity and consistence of the expression of MPS-1 and ITGB4 in histology and cytology, we explore the function of MPS-1 in regulating metatasis of gastric cancer cells mediated by ITGB4 via in vitro and in vivo experiments. Finally, by exploring the regulation of the expression of ITGB4 by MPS-1 and the flunence of MPS-1 activating the transcriptional factor NF-κB through ITGB4, we endeavour to confirm the mechanism of the metastasis of gastric cancer cells. In summary, this work is to investigate the role and mechanism of MPS-1 mediated by ITGB4 in regulating gastric cancer metastasis. Thus, this will provied novel thinking and strategy for the biological therapy of gastric cancer.

肿瘤转移是胃癌患者死亡的主要原因。前期本课题组利用SEREX方法筛选出一个胃癌相关基因MPS-1 (Metallopanstimulin-1), 并已证实MPS-1与胃癌的发生及转移密切相关。通过基因表达谱的数据分析发现转移相关基因整合素β4（ITGB4）可能为介导MPS-1在胃癌细胞转移中作用的下游基因。本项目以此为基础，深入研究MPS-1在胃癌细胞转移中的作用及其机制。首先，利用体内外实验研究MPS-1在胃癌细胞转移中的作用。其次，基于MPS-1和ITGB4表达的相关性和一致性，利用体内外的方法研究MPS-1通过ITGB4调控胃癌细胞的转移。最后，通过研究MPS-1对ITGB4表达的调控及对其下游转录因子NF-κB活性的影响，明确MPS-1调控胃癌细胞转移的具体机制。整合上述研究结果，阐明MPS-1通过ITGB4调控胃癌细胞转移的作用及机制,从而为胃癌的生物学治疗提供新的思路和策略。

前期本课题组利用SEREX方法筛选出一个胃癌相关基因MPS-1 (Metallopanstimulin-1), 并已证实MPS-1与胃癌的发生及转移密切相关。本项目以此为基础，首先在体内外实验研究中发现MPS-1下调能够显著抑制胃癌细胞的侵袭和转移能力。而且，MPS-1过表达能够明显提高永生化的胃黏膜上皮细胞GES-1及胃癌细胞的增殖、侵袭和迁移能力。进一步利用MPS-1下调的基因表达谱分析筛选出显著下调的MPS-1的潜在靶基因，通过mRNA和蛋白水平的验证发现整合素 beta 4（ITGB4）的变化最为显著，并且我们发现二者在胃癌细胞和组织中的表达具有相关性。ITGB4在胃癌组织和细胞中表达水平较高，而且ITGB4的上调或下调能显著影响胃癌细胞的增殖、侵袭和迁移能力。我们进一步研究证实MPS-1能够通过调控ITGB4的表达影响胃癌细胞的增殖、侵袭和迁移。综上所述，我们初步阐明了MPS-1通过ITGB4调控胃癌细胞转移的作用及机制, 从而为胃癌的生物学治疗提供了一个新的潜在靶点。相关研究成果已在杂志 Carcinogenesis （2013；34：2851–2860）上发表。