FOXL1抑制胰腺癌肿瘤发生的分子机制研究

Pancreatic cancer is one of the most lethal malignancies. Better understanding of molecular mechanism of carcinogenesis is desperately needed for the development of novel therapies to improve outcomes in pancreatic cancer patients. In recent years, many important studies have reported that Fox transcription factor family plays critical roles in tumor biology especially in maintaining tumor stem cells. In order to identify Fox genes associated with the aggressiveness of pancreatic cancer, we tested gene expression of several Fox genes in human pancreatic tumor samples and found that high FOXL1 is associated with better clinical outcome (Cox regression, P<0.05). Our preliminary data for the first time demonstrated that FOXL1 suppresses pancreatic tumor developments. Over-expression of FOXL1 significantly inhibits migration and invasion of pancreatic cancer cells. FOXL1also inhibits tumor proliferation by promoting apoptosis in pancreatic cancer. The present study will focus on the function of FOXL1 in regulating cancer stem cell and cell cycle. We will identify FOXL1 downstream target genes and elucidate the upstream signaling pathways regulating FOXL1 expression and post-translational modification, especially TGF-beta and IGF signals. We will further identify phosphorylation, acetylation and ubiquitination sites for FOXL1 and investigate the functional significance of post-translational modification. Taken together, our study will systematically elucidate the molecular mechanisms underlying inhibitory effect of FOXL1 in pancreatic cancer and provide highly valuable insights into the design of more effective treatments for this deadly disease.

深入探究胰腺癌发生发展的分子机制对于开发新型有效的抗胰腺癌治疗方案至关重要。Fox转录因子家族在肿瘤特别是肿瘤干细胞中显现的重要作用引起广泛关注而成为研究热点。为鉴定在胰腺癌中起关键作用的Fox基因，通过对临床样本中的多个Fox基因进行了定量PCR分析，发现表达高水平FOXL1可显著延长患者的存活期。我们前期证实了FOXL1对胰腺癌的抑制作用。发现在癌细胞中提高FOXL1表达量，能抑制癌细胞的迁移、粘附和侵袭，并通过促进细胞凋亡，最终抑制肿瘤细胞的增殖。本课题将深入研究FOXL1在肿瘤干细胞和细胞周期中的作用机制，揭示FOXL1的上游调节因子和下游靶向基因，探明TGF-beta和IGF信号对FOXL1的转录调节的作用，鉴定FOXL1的磷酸化、乙酰化及泛素化位点，深入分析转录后修饰对其功能的影响，系统阐明FOXL1对胰腺癌抑制作用的分子机理，为开发有效合理的治疗方案提供理论和实验依据。

本课题发现了FOXL1基因在胰腺癌肿瘤组织中高表达，并显著提高胰腺癌患者的存活期。FOXL1能够抑制胰腺癌肿瘤细胞的体外生长及集落形成。FOXL1基因通过上调促凋亡基因TRAIL的表达诱导肿瘤细胞的凋亡，阐述了FOXL1诱导肿瘤细胞凋亡的机制。同时，我们首次发现了C8orf4在肝癌干细胞中低表达，并阐释了C8orf4通过抑制Notch2的入核抑制肝癌干细胞的自我更新。我们也证实了新转录因子Zic2能够招募NURF复合物到多能因子Oct4的启动子区，激活Oct4的表达，驱动肿瘤干细胞的重编程。通过该项目的完成揭示了胰腺癌和肝癌的致癌机制，为开发有效合理的治疗方案提供理论和实验依据。