血小板环氧合酶1耦联凝血噁烷通路共同驱动结直肠癌变的分子机制研究

Cyclooxygenase-1 (COX-1) is constitutively expressed both in normal colonic mucosa and tumor tissue. However, recent finding that genetic disruption of ptgs-1 (gene coding for COX-1) could reduce mouse intestinal polyposis by 80% strongly indicates a critical role of COX-1 in colon carcinogenesis, its exact mechanism of action still remains unclear. Thrombosis is a common complication in colorectal cancer patients whose blood normally has a higher platelet count as well as platelet COX-1-derivated thromboxane A2 (TXA2) level. Inspired by findings above, we hypothesize that platelet COX-1 might drive colorectal tumorigenesis via the activation of TXA2 signaling pathway. This study was conducted to evaluate the clinical potential of selective COX-1 inhibition in colon cancer chemoprevention, and further clarify its underlying mechanisms. Taken together, the present work might give an insight into the pathophysiological role of platelet COX-1 in colon cancer development, and provide a strong rational for application of selective COX-1 inhibitors in colorectal cancer chemoprevention.

环氧合酶1（COX-1）在正常结直肠粘膜和肿瘤组织的表达通常无明显差异，然而近期基因敲除小鼠研究却意外揭示COX-1对结直肠癌的发生发展至关重要，但其作用机制尚未明了。临床观察到，中晚期结直肠癌患者的血液常呈“高凝状态”且血小板激增，而后者恰为机体内COX-1丰度最高的组织之一。受上述现象启发，本课题组提出COX-1驱动结直肠癌变可能的新机制：尽管COX-1在癌变部位变化不大，但机体外周血中血小板异常升高，使得血小板COX-1及耦联的凝血噁烷合酶（TXS）相应上调，促进凝血噁烷 (TXA2）的生物合成，TXA2随血液循环至凝血噁烷受体（TP）高表达的癌变部位，持续激活TP启动下游信号通路，促进侵袭转移。本项目拟在人家族性腺瘤性息肉病小鼠模型中综合评价COX-1及下游TXA2支路作为结直肠肿瘤预防靶标的潜力，探讨其参与癌变的分子机制，为未来药物开发和疾病预防策略的制定提供科学依据和理论基础。

环氧合酶1（COX-1）在正常结直肠粘膜和肿瘤组织的表达通常无明显差异，然而近期基因敲除 小鼠研究却意外揭示COX-1对结直肠癌的发生发展至关重要，但其作用机制尚未明了。本课题组提出血小板COX-1耦联凝血噁烷通路共同驱动结直肠癌变的假说：尽管COX-1在癌变部位变化不大，但机体外周血中血小板异常升高，使得血小板COX-1及耦联的凝血噁烷合酶（TXS）相应上调，促进凝血噁烷 (TXA2）的生物合成，TXA2随血液循环至凝血 噁烷受体（TP）高表达的癌变部位，持续激活TP启动下游信号通路，促进侵袭转移。本研究项目系统分析COX-1及下游TXA2支路在癌变中的动态变化规律，并进而在小鼠模型中综合评价COX-1及下游TXA2支路作为结直肠肿瘤预防靶标的潜力，探讨其参与癌变的分子机制，为未来药物开发和疾病预防策略的制定提供科学依据和理论基础。在国内外核心学术刊物上共发表研究论文4篇，其中SCI收录论文3篇，培养研究生3名。