胰腺星状细胞高表达Galectin-1通过SDF-1/CXCR4轴诱导胰腺癌肝转移的机制研究

Pancreatic stellate cells (PSC) paly an important role in targeting hepatic metastasis of pancreatic cancer, but the specific molecular mechanism is unclear. Our preliminary experiments indicated that Galectin-1 was high expressed in PSC and the hepatic metastasis of pancreatic cancer. Galectin-1 could increase the expression of C-X-C chemokine receptor type 4 (CXCR4) significantly in pancreatic cancer cells, and induce the activation of PSC and hepatic stellate cells (HSC) accompanied with increased expression of SDF-1. However, SDF-1/CXCR4 signaling axis plays an important role in organ-specific metastasis of pancreatic cancer. To this end, we propose a hypothesis that high expression of Galectin-1 of PSC in pancreatic cancer microenvironment activated PSC/HSC, and induced pancreatic cancer cells homing to liver by SDF-1/CXCR4 signaling axis. To validate this hypothesis, we will investigate the molecular mechanism of liver-specific metastasis of pancreatic cancer by Galectin-1 expression in PSC from the molecular, cellular, organizations and the whole animal level aspects. The methods we will ues 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 pancreatic cancer and provide the new research strategies and therapeutic targets.

胰腺星状细胞(PSC)在胰腺癌靶向肝转移发挥了重要作用，但具体分子机制尚不清楚。我们预实验发现胰腺癌中PSC及肝转移灶Galectin-1高表达；Galectin-1能促进胰腺癌细胞CXCR4表达，诱导PSC/肝星状细胞（HSC）活化及SDF-1表达增加；而SDF-1/CXCR4信号轴在胰腺癌器官特异性转移中发挥重要作用。为此，我们提出假说：胰腺癌微环境中PSC高表达Galectin-1激活PSC/HSC，通过SDF-1/CXCR4信号轴诱导胰腺癌细胞靶向肝特异性转移。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、组织以及动物整体水平等多方面探讨PSC通过Galectin-1促进胰腺癌肝转移的分子机制。本研究将从肿瘤微环境这个新视点揭示胰腺癌肝转移的发生机制，为胰腺癌治疗提供新的研究思路和治疗靶点。

Galectin-1在多种肿瘤的发生发展中起着重要作用，我们前期研究发现了激活的胰腺星状细胞表达大量Galectin-1，但Galectin-1在胰腺星状细胞中如何发挥作用仍尚无研究报道，如促进分泌趋化因子及其与癌症进展之间的联系等。我们通过趋化因子芯片、Transwell侵袭转移实验等发现，Galectin-1可诱导星状细胞中SDF-1大量释放，并导致胰腺癌细胞的侵袭转移能力显著增加；NF-κB通路活性实验发现，NF-κB通路在上述进程中起着至关重要的作用。qRT-PCR，ELISA、免疫荧光实验等亦验证了上述结果；同时，我们还通过Galectin-1慢病毒敲低实验、SDF-1中和抗体实验、CXCR4抑制剂实验及NF-κB抑制剂实验进一步证明了以上结果。综上所述，Galectin-1通过NF-κB通路刺激胰腺星状细胞中SDF-1的分泌，进一步促进胰腺癌的侵袭转移能力。本研究证实了胰腺星状细胞中Galectin-1在胰腺癌发生发展过程的重要作用，亦为胰腺癌靶向治疗提供了潜在靶点。