HIF-1调控Galectin-1与S1PR1-STAT3信号轴对话并诱导胃癌特异性肝转移的机制研究

Hypoxia palys an important role in targeting hepatic metastasis of gastric cancer, but the specific molecular mechanism and the role of the target are unclear. Hypoxia inducible factor-1 (HIF-1) could increase the expression of Galectin-1. Our preliminary experiments indicated that high expression of Galectin-1 in gastric cancer promote the expression of signal transducer and activator of transcription-3 (STAT3) in cancer cells. STAT3 could induce S1PR1 expression, which mediated Stat3 activation persistently in tumors. In addition, S1PR1-STAT3 signaling axis could induce myeloid cells recruit to liver and initiate the hepatic pre-metastatic niche, and then induce the cancer cells colonization at future metastatic sites. To this end, we propose a hypothesis that HIF-1 mediates expression of galectin-1 and promotes the liver metastasis of gastric cancer by the action of S1PR1-STAT3 signaling axis. To validate this hypothesis, we will investigate the molecular mechanism of liver-specific metastasis of gastric cancer by Galectin-1 expression mediated by hypoxia from the molecular, cellular, organizations and the whole animal level aspects. The methods we will use are as follows: the observation of clinical pathology, the techniques of gene transfection, gene silencing and small animal in vivo fluorescence imaging, and the experiments of in vitro co-culture and in vivo tumor formation in situ. By this study, we will clarify the molecular mechanism of liver-specific metastasis of gastric cancer from the new sight of pre-metastatic niche and provide the new research strategies and therapeutic targets.

缺氧在胃癌靶向肝转移中发挥重要作用，但具体分子机制及作用靶点尚不清楚。缺氧诱导因子-1（HIF-1）能诱导Galectin-1表达增加；我们预实验发现胃癌中Galectin-1高表达能促进癌细胞STAT3表达；STAT3可诱导S1PR1表达并持续激活STAT3；S1PR1-STAT3信号轴能诱导髓样细胞向肝募集及营造肝预转移小生境，并可诱导癌细胞靶向归巢。为此，我们提出假说：缺氧诱导因子HIF-1调控Galectin-1表达，通过S1PR1-STAT3信号轴诱导胃癌细胞靶向肝转移。为验证这一假说，我们拟通过临床病理学观察，利用基因转染、基因沉默及小动物活体荧光成像等技术，体外共培养和体内原位成瘤实验，从分子、细胞、组织及动物水平等多方面探讨缺氧通过Galectin-1促进胃癌肝转移的分子机制。本研究从预转移小生境这个新视点揭示胃癌靶向肝转移的发生机制，为胃癌治疗提供新的研究思路和治疗靶点。

胃癌是我国乃至全世界发病率前三的癌症病种，且大多数胃癌诊断时已伴有远处的转移，预后较差。缺氧在胃癌靶向肝转移中发挥重要作用，但具体分子机制及作用靶点尚不清楚。缺氧诱导因子-1（HIF-1）能诱导Galectin-1表达增加；我们预实验发现胃癌中Galectin-1高表达能促进癌细胞STAT3表达；STAT3可诱导S1PR1表达并持续激活STAT3；S1PR1-STAT3信号轴能诱导髓样细胞向肝募集及营造肝预转移微环境，并可诱导癌细胞靶向归巢。为此，我们提出假说：缺氧诱导因子HIF-1调控Galectin-1表达，通过S1PR1-STAT3信号轴诱导胃癌细胞靶向肝转移。我们通过收集本中心的胃癌标本，肝转移标本及癌旁组织标本，构建 HIF-1α/ HIF-1β、 Galectin-1、 S1PR1/STAT3、 SDF-1/CXCR4过表达的干扰RNA， 沉默慢病毒载体并完成鉴定工作，构建稳定表达的OE/KD实验细胞，建立共培养体系，检测实验细胞中galctin-1的表达以及侵袭，转移，增值能力的变化程度，并在蛋白质表达的水平研究HIF-1与Galectin-1的分子通路的结合位点，最后通过动物实验来验证体外实验的结论。.研究期间发表国内外学术论文4篇，影响因子共10分。实验结论基本与预计设想吻合。在一定程度上阐述了胃癌细胞的癌症学特性与Galectin-1的关系以及Galectin-1分子在胃癌的发生，转移，侵袭中的作用。为将来的进一步研究提供了理论依据和设想前提。