GXYLT1及其突变体介导Notch-mTOR通路交互作用调节结直肠癌Warburg效应促进其侵袭转移的机制研究

Warburg effect and metastasis are the characteristics of tumor cells. Our previous study identified that glycoside-xylosytransferase (GXYLT1) had a high frequency of mutation in the colorectal cancer tissue. The mutation of GXYLT1 resulted in the termination of the protein expression. However, the roles of GXYLT1 and its mutant in tumor has not been elucidated. Our previous results suggested that GXYLT1 was involved in glycolysis and metastasis of colorectal cancer, and regulated Notch and mTOR signaling pathways. This study will explore the mechanism of GXYLT1 and its mutants mediating the crosstalk between Notch and mTOR pathway to regulate glycolysis and metastasis in colorectal cancer. First, we decide to clarify the effects of GXYLT1 and its mutants in biological activities in colorectal cancer. Second, we want to detect the regulation of GXYLT1 and its mutant in Notch and mTOR pathways and the crosstalk between the two pathways. The xylosyl modification of crucial molecules by GXYLT1 needs to be explored. Third, we decide to understand whether GXYLT1 is involved in the modification and regulation of other proteins. Finally, we want to demonstrate the expression levels and mutantion of GXYLT1 in colorectal cancers, as well as their clinical significance. The purpose of this study was to elucidate the regulation of metabolism and metastasis colorectal cancer, and the underlying mechanism of GXYLT1-Notch-mTOR network. Our study will provide new potential strategies for diagnosis and treatment in colorectal cancer.

Warburg效应和侵袭转移是肿瘤细胞的特征。前期工作发现木糖基转移酶GXYLT1在结直肠癌组织存在较高的突变频率，突变后导致蛋白表达提前终止。但GXYLT1及其突变在肿瘤中的作用，目前尚不清楚。预实验提示GXYLT1参与结直肠癌糖酵解和侵袭转移，并调控Notch和mTOR通路。本项目我们拟探讨GXYLT1及其突变体介导Notch-mTOR通路交互作用调节结直肠癌糖酵解促进其侵袭转移的机制。首先，明确GXYLT1及其突变体对肿瘤生物学特性的影响；其次，明确GXYLT1及其突变体对Notch和mTOR通路及其交互调控作用，GXYLT1对通路关键分子的木糖基修饰；再次，明确GXYLT1对其它蛋白是否存在修饰调控作用。最后，探讨GXYLT1在肿瘤组织中突变和表达的临床意义。本研究旨在阐明以GXYLT1-Notch-mTOR为核心的结直肠癌能量代谢及侵袭转移的调控方式，并为肿瘤诊疗提供新的策略。

本项目进展过程中开展了一系列研究工作。首先，探索了45例结直肠癌患者的基因组改变情况，明确了GXYLT1在结直肠癌患者中存在高频突变。其次，明确了GXYLT1及突变体GXYLT1（S212*）高表达可促进结直肠癌细胞侵袭转移，并通过脾脏肝转移动物模型进一步证实。在课题进展中，我们发现GXYLT1对结直肠癌细胞的促转移作用依赖于Notch通路，而突变体GXYLT1（S212*）的促转移作用主要依赖于MAPK通路。此外，GXYLT1参与mTOR通路调节。最后，数据库分析及样本检测明确了GXYLT1在肿瘤组织高表达，且GXYLT1高表达提示结直肠癌患者预后不良。在研究过程中我们发现，GXYLT1亦通过调控PD-L1水平调节免疫细胞活性及免疫微环境，对此我们展开了进一步的研究，上述工作已获得国家自然科学基金资助。.综上，本项目明确了45例结直肠癌患者的基因组改变情况，发现GXYLT1在结直肠癌患者中存在高频突变，阐明了GXYLT1及突变体 GXYLT1（S212*）对结直肠癌发生发展的影响以及作用方式。同时明确了GXYLT1在结直肠癌肿瘤组织中的表达及其临床意义。该研究为深入了解木糖基转移酶GXYLT1及突变体在肿瘤发生发展中的作用及相关分子机制奠定了一定基础，具有一定的潜在应用价值。