C1GALT1调控自噬促进胃癌侵袭转移的机制研究

Invasion and metastasis are the main causes accounting for the poor prognosis and death in patients with gastric cancer. Core 1 β1, 3-galactosyltransferase (C1GALT1) is associated with the invasion and metastasis of gastric cancer, but the underlying mechanism is still unknown. In our previous studies, we found that the expression of C1GALT1 was specifically increased in the highly aggressive gastric cancer cells. We also observed that knockdown of C1GALT1 could inhibit the invasion and metastasis of gastric cancer, and block the autophagy-related pathway PI3K/Akt/mTOR. In addition, reduction of C1GALT1 resulted in altered expression of the autophagy markers. Therefore, we propose the scientific hypothesis that C1GALT1 may promote the invasion and metastasis of gastric cancer by targeting autophagy via the PI3K/Akt/mTOR pathway. In this study, the association between C1GALT1 and the invasion and metastasis of gastric cancer will be investigated using clinical tissue specimens. Then the effects of C1GALT1 on the invasion and metastasis of gastric cancer will be confirmed by in vitro and in vivo experiments. Finally, the relationship between autophagy and C1GALT1-mediated invasion and metastasis of gastric cancer will be explored. In conclusion, our results will not only help to provide a novel biomarker for predicting metastasis and recurrence of gastric cancer, but also establish a new mechanism for C1GALT1 in regulating the invasion and metastasis of gastric cancer. These findings may offer sufficient scientific evidence to identify C1GALT1 as a new target for anti-metastatic therapy.

侵袭转移是胃癌患者预后不良和死亡的重要因素。糖基转移酶C1GALT1与胃癌侵袭转移密切相关，但机理不明。我们前期发现：C1GALT1在高侵袭性胃癌细胞中的表达特异性增加，下调C1GALT1的表达可抑制胃癌侵袭转移，且阻断了自噬相关通路PI3K/Akt/mTOR；随后研究发现，C1GALT1的表达缺失导致自噬标志物的表达改变。因此我们提出科学假说：C1GALT1通过PI3K/Akt/mTOR通路调控自噬而促进胃癌的侵袭转移。本项目将以C1GALT1为切入点，首先利用临床标本分析其与胃癌侵袭转移的相关性；其次通过体内外实验探讨C1GALT1在胃癌侵袭转移中的作用；最后深入研究自噬与C1GALT1介导的胃癌侵袭转移的内在关联。本项目的完成，将为临床预测胃癌转移复发提供一个新标志物，并建立C1GALT1调控胃癌侵袭转移的新机制，从而为确立C1GALT1作为抗胃癌转移治疗的新靶点提供充分的科学依据。

胃癌是一种具有高侵袭性和致命性的恶性肿瘤。侵袭转移是胃癌预后不良、患者死亡的重要因素。糖基转移酶C1GALT1与胃癌的侵袭转移密切相关，但机理不明。本项目主要揭示了C1GALT1在胃癌中的生物学功能及调控机制，并初步探讨了C1GALT1的小分子抑制剂Itraconazole对胃癌侵袭转移的影响。①采用公共数据库和临床组织标本，证实C1GALT1的mRNA和蛋白表达均在胃癌组织中上调，C1GALT1蛋白表达增加与较高的TNM分期，淋巴结转移，肿瘤复发以及较差的总体生存率相关。②基于功能获得和功能丧失实验，证实C1GALT1促进胃癌细胞的增殖、迁移和侵袭。③通过凝集素pull-down结合质谱技术，证实integrin α5是C1GALT1的下游靶点，并且C1GALT1能够修饰integrin α5上的O-糖基化从而调节PI3K/AKT通路的活性，进一步抑制integrin α5在体内和体外均可逆转C1GALT1介导的肿瘤生长和转移。④转录因子SP1结合C1GALT1的启动子区激活其表达，而miR-152直接结合C1GALT1的3′-UTR负调控其表达。⑤功能实验发现，Itraconazole抑制胃癌细胞的增殖、侵袭和迁移，诱导G0/G1期阻滞，促进凋亡；生物信息学分析显示，C1GALT1与O-糖基化途径及自噬通路密切相关；机理研究表明，Itraconazole下调胃癌细胞中C1GALT1的蛋白表达，并可阻断O-糖基化，提高自噬水平。本项目阐明了C1GALT1调控胃癌侵袭转移的分子机制，为预测胃癌转移复发提供了新的标志物。