Tn抗原通过DR4/DR5调控结直肠癌细胞对TRAIL敏感性的机制研究

Death receptor 4(DR4) and DR5 regulate the sensitivity of tumor cells to tumor necrosis factor related apoptosis-induced ligand (TRAIL). Aberrant O-glycosylation has been reported to affect the oligomerization of DR4/DR5. Our previous study found that the abnormal O-glycan structure, Tn antigen, is widely expressed in colorectal cancer and promotes the oncogenic features such as proliferation, migration and invasion. Tn antigen expression enhances the resistance of colorectal cancer cells to TRAIL, which is caused by the Tn antigen on DR4/DR5. Based on this, we hypothesized that the O-glycan structure on DR4/DR5 is the key to regulate the sensitivity of tumor cells to TRAIL. Tn antigen regulates apoptosis by affecting the oligomerization status of DR4/DR5. This study is intended to be validated as follows: 1. In vitro experiments to investigate the effect of Tn antigen expression on TRAIL-induced apoptosis pathway; 2. Verify O-glycan structure on death receptor DR4/DR5; elucidate the effects of Tn antigen on DR4/DR5 receptor function and oligomerization status; 3. Study the Tn antigen induced tumor cells tolerant to TRAIL via DR4/DR5 in vivo. This will provide new clues for the clinical application of TRAIL-targeted therapy.

死亡受体DR4/DR5参与调控肿瘤细胞对肿瘤坏死因子相关凋亡诱导配体（TRAIL）的敏感性。业已报道，O-糖基化异常影响DR4/DR5的聚集状态。我们的前期研究发现，异常O-聚糖结构——Tn抗原在结直肠癌组织中广泛表达，并增强肿瘤细胞增殖、迁移、侵袭能力。表达Tn抗原的肿瘤细胞对TRAIL不敏感，该现象与DR4/DR5上的Tn抗原相关。据此我们推测：DR4/DR5上的O-聚糖结构是调控肿瘤细胞对TRAIL敏感性的关键，Tn抗原通过影响DR4/DR5的聚集状态调控细胞凋亡。本课题拟做如下验证：1.体外实验研究Tn抗原对TRAIL诱导的细胞凋亡通路的影响；2.验证死亡受体DR4/DR5上的O-聚糖结构；阐明Tn抗原对DR4/DR5受体功能、聚集状态的调控作用；3.体内实验验证死亡受体DR4/DR5上Tn抗原表达诱导肿瘤细胞对TRAIL耐受。从而为推动靶向TRAIL治疗在临床中的应用提供新线索。

结直肠癌中常发生异常的O-糖基化过程并表达肿瘤相关抗原——Tn抗原，Tn抗原在结直肠癌的发生及进展中具有重要作用，促进肿瘤增殖、迁移、侵袭等恶性行为，而目前Tn抗原对肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的细胞凋亡影响尚未阐明。我们的研究发现，表达异常O-聚糖Tn抗原的肿瘤细胞对TRAIL诱导的细胞凋亡不敏感，这主要是通过影响与TRAIL结合的死亡受体DR4/DR5的表达及聚集状态，从而削弱了下游Caspase通路的激活，最终导致肿瘤细胞对TRAIL耐受并存活，我们的研究证实肿瘤细胞中异常的O-糖基化过程，影响DR4/DR5受体上的正常O-聚糖形成，从而直接影响DR4/DR5受体的结构和功能。综上，本课题揭示了异常O-聚糖Tn抗原对结直肠癌肿瘤细胞对TRAIL诱导的细胞凋亡中的影响及机制，为结直肠癌靶向治疗提供了新的治疗靶点。