Feng Xuefei, Chen Jinyan, Lian Jianhong, Dong Tianyue, Gao Yingzhen, Zhang Xiaojuan, Zhai Yuanfang, Zou Binbin, Guo Yanlin, Xu Enwei, Cui Yongping, Zhang Ling
Department of Pathology, Basic Medical Sciences Center, Key Laboratory of Cellular Physiology of Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
Department of Thoracic Surgery, Shanxi Cancer Hospital, Taiyuan, 030001, Shanxi, China.
Cell Mol Life Sci. 2024 Dec 5;81(1):481. doi: 10.1007/s00018-024-05534-3.
Aberrant glycosylation is one of the hallmarks of cancer. The profile of glycoprotein expression caused by abnormal glycosylation has been revealed, while abnormal glycogenes that may disturb the structure of glycans have not yet been identified in esophageal squamous cell carcinoma (ESCC).
Genomic alterations driven by differentially expressed glycogenes in ESCC were compared with matched normal tissues by multi-omics analysis. Immunohistochemistry, MTT, colony formation, transwell assays, subcutaneous tumor formation experiments and tail vein injection were used to study the expression and the effect on the proliferation and metastasis of the differentially expressed glycogenes POFUT1 and RPN1 in ESCC. In the alkyne fucose labeling experiment, AAL lectin affinity chromatography and immunoprecipitation were used to explore the mechanism of POFUT1 in ESCC.
The expression of the POFUT1 and RPN1 glycogenes were upregulated, as determined by genomic copy number gain and proteomics analysis. The overexpression of POFUT1 or RPN1 was associated with poor prognosis in ESCC patients and affected the proliferation and metastasis of ESCC in vivo and in vitro. The overexpression of POFUT1 increased the overall fucosylation level and activated the Notch signaling pathway, which partially mediated POFUT1 induced pro-migration in ESCC. The regulation of malignant progression of ESCC by RPN1 may be related to the TNF signaling pathway, p53 signaling pathway, etc. CONCLUSIONS: Our study fills a gap in the study of abnormal glycogenes and highlights the potential role of the POFUT1/Notch axis in ESCC. Moreover, our study identifies POFUT1 and RPN1 as promising anticancer targets in ESCC.
异常糖基化是癌症的标志之一。由异常糖基化引起的糖蛋白表达谱已被揭示，但在食管鳞状细胞癌（ESCC）中，尚未鉴定出可能干扰聚糖结构的异常糖基因。
通过多组学分析，将ESCC中差异表达的糖基因驱动的基因组改变与匹配的正常组织进行比较。采用免疫组织化学、MTT、集落形成、Transwell实验、皮下肿瘤形成实验和尾静脉注射等方法，研究差异表达的糖基因POFUT1和RPN1在ESCC中的表达及其对增殖和转移的影响。在炔基岩藻糖标记实验中，采用AAL凝集素亲和色谱和免疫沉淀法探索POFUT1在ESCC中的作用机制。
通过基因组拷贝数增加和蛋白质组学分析确定，POFUT1和RPN1糖基因的表达上调。POFUT1或RPN1的过表达与ESCC患者的不良预后相关，并在体内和体外影响ESCC的增殖和转移。POFUT1的过表达增加了整体岩藻糖基化水平并激活了Notch信号通路，这部分介导了POFUT1诱导的ESCC细胞迁移。RPN1对ESCC恶性进展的调控可能与TNF信号通路、p53信号通路等有关。结论：我们的研究填补了异常糖基因研究的空白，突出了POFUT1/Notch轴在ESCC中的潜在作用。此外，我们的研究将POFUT1和RPN1确定为ESCC中有前景的抗癌靶点。
