星状细胞高表达Galectin-1竞争性结合Galectin-3结合位点并促进胰腺癌侵袭转移机制研究

The interaction of pancreatic stellate cells (PSC) and cancer cells promotes the invasion and metastasis of pancreatic cancer, but the role of targets and the specific molecular mechanisms are unclear. It has been reported that Galectin-1 and Galectin-3 are important adhesion molecules with common binding sites in extracellular matrix (ECM), and both of them are closely related to the invasion and metastasis of pancreatic cancer. We found that Galectin-1 is highly expressed in PSC, while Galectin-3 is highly expressed in the cancer cells located in the center of tumor, and low expressed in the cancer cells in front of invasion edge of pancreatic cancer. It was also found that PSC with highly expression of Galectin-1 up-regulate Galectin-3 expression in pancreatic cancer cells in vitro experiment. To this end, we propose a hypothesis that highly expressed Galectin-1 in PSC up-regulate Galectin-3 expression in the cancer cells in front of invasion edge of pancreatic cancer and competitively bond the Galectin-3 binding sites in ECM, which assisted the cancer cells penetrate the ECM for further invasion and metastasis. With the observation of clinical pathology, the techniques of gene transfection, gene silencing, and the experiments of in vitro co-culture and in vivo tumor formation in situ, we intend to study the mechanisms of Galectin-1 and Galectin-3 synergistically promoting pancreatic cancer invasion and metastasis. By this study, we will clarify the molecular mechanism of invasion and metastasis of pancreatic cancer that promoted by in interaction of PSC and pancreatic cancer cells, and provide the new research strategies and therapeutic targets for pancreatic cancer.

星状细胞（PSC）与癌细胞相互作用可促进胰腺癌侵袭转移，但其作用靶点及分子机制尚不清楚。文献报道粘附分子Galectin-1和Galectin-3在ECM中有共同结合位点，与胰腺癌侵袭转移密切相关。预实验发现胰腺癌中Galectin-1在PSC高表达，Galectin-3在中央癌细胞高表达，在边缘癌细胞低表达；Galectin-1高表达PSC能上调癌细胞Galectin-3表达。为此，我们提出假说：PSC通过Galectin-1上调侵袭边缘癌细胞Galectin-3表达，并竞争性结合ECM中Galectin-3结合位点，促进癌细胞侵袭转移。为验证该假说，我们拟通过病理学观察、基因转染/沉默、体外共培养和体内成瘤实验，探讨Galectin-1与Galectin-3协同促进胰腺癌侵袭转移机制。本研究可阐明PSC与癌细胞相互作用促进胰腺癌侵袭转移的分子机制，为胰腺癌综合治疗提供新策略和治疗靶点。

研究背景：胰腺癌是人类最致命的恶性肿瘤之一，预后极差。胰腺癌微环境中肿瘤细胞-间质细胞之间的关系受到广泛关注。星状细胞（PSC）与癌细胞相互作用可促进胰腺癌侵袭转移，但其作用靶点及分子机制尚不清楚。文献报道粘附分子Galectin-1和Galectin-3在ECM中有共同结合位点，与胰腺癌侵袭 转移密切相关。预实验发现胰腺癌中Galectin-1在PSC高表达，Galectin-3在中央癌细胞高表达，在边缘癌细胞低表达；Galectin-1高表达PSC能上调癌细胞Galectin-3表达。为此，我们提出假说：PSC通过Galectin-1上调侵袭边缘癌细胞Galectin-3表达，并竞争性结合ECM中Gale ctin-3结合位点，促进癌细胞侵袭转移。..研究内容：1、胰腺癌组织中 Galectin-1 表达、Galectin-3 表达、Galectin-3 结合位点含量与胰腺癌进展之间的关系；2、胰腺癌细胞和星状细胞共培养，观察共培养体系中两者基因谱表达情况；3、胰腺星状细胞表达 Galectin-1 与胰腺癌细胞表达 Galectin-3 协同促进胰腺 癌细胞侵袭转移的体外实验；4、PSC 通过 Galectin-1 竞争性结合 Galectin-3 结合位点并诱导胰腺癌细胞 Galectin-3 表达，进而促进胰腺癌细胞侵袭转移的体内实验研究。..重要结果：1、hCPSC衍生的galectin-1在微环境中的胰腺癌通过诱导T细胞的凋亡和无反应性而促进癌细胞逃避免疫监视；2、PSC源性半乳糖凝集素-1通过激活NF-κB通路诱导胰腺导管腺癌细胞的上皮-间质转化，进而促进胰腺癌细胞侵袭转移；3、活化的胰腺星状细胞中Galectin-1的表达通过TGF-β1/ Smad途径促进慢性胰腺炎/胰腺癌的纤维化，在胰腺癌组织中进一步促进胰腺癌纤维化微环境的形成，并促进胰腺癌细胞的恶性行为；4、胰腺癌微环境中PSC表达Galectin-1和胰腺癌细胞表达Galectin-3协同促进胰腺癌侵袭转移。..研究意义：本项目发现：PSC和胰腺癌细胞相互作用后，可促进PSC中Galectin-1高表达，而PSC高表达Galectin-1可促进胰腺癌细胞免疫逃逸、侵袭转移，并可通过竞争性结合胰腺癌细胞中的Galectin-3结合位点协同促进胰腺癌细胞的侵袭转移，本研究对于探索胰腺癌和PSC