修剪过的n -聚糖定义侵袭性胃癌并预测临床结果。

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-08-22 eCollection Date: 2025-01-01 DOI:10.7150/thno.111670
Dylan Ferreira, Beatriz Marinho-Santos, Marta Relvas-Santos, Bernardo Orr, Andreia Brandão, Luís Pedro Afonso, Lúcio Lara Santos, José Alexandre Ferreira
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引用次数: 0

摘要

理由:胃癌(GC)是癌症相关死亡的主要原因,特别是在预后和靶向治疗仍然具有挑战性的晚期。糖萼是一个密集的聚糖和糖蛋白网络,对肿瘤进展和免疫逃避至关重要,但其分子特征尚不清楚。本研究调查了基于糖基的生物标志物的侵袭性,重点研究了少核苷n-糖基化模式,这是一种以前未被充分探索的癌症糖基化模式。方法:对不同侵袭性的胃肿瘤进行高通量n -糖苷分析,然后采用加兰花凝集素(GNL)免疫染色来评估不同肿瘤分期的少糖内苷聚糖。与临床相关的GC生物标志物(E-cadherin, p53, MSI, sTn, sLeA)进行比较分析。TCGA分析将关键的少西曼糖相关糖基转移酶与临床结果联系起来。糖蛋白组学鉴定了携带少西曼糖的糖蛋白,随后在肿瘤组织中使用免疫分析验证了其临床相关性。此外,分析血清样本以评估GNL反应性和相关糖蛋白的无创潜力。结果:侵袭性胃肿瘤显著富含少糖内苷n -聚糖,这一特征此前未在这种恶性肿瘤中报道。凝集素免疫印迹证实了它们的疾病特异性,表达随肿瘤进展而增加。GNL染色在预后准确性方面优于已建立的生物标志物。400多例患者的TCGA分析显示,少西曼糖相关糖基转移酶高表达与预后不良有很强的相关性。糖蛋白组学出人意料地揭示了主要存在于细胞内核糖体蛋白上的少糖糖n -聚糖,尽管关键的膜蛋白如MMP9显示了异常的少糖糖化。MMP9的表达随肿瘤分期和分级而增加,肿瘤共表达MMP9和少核桃苷聚糖预后最差。在血清中,只有MMP9显示出作为循环生物标志物的诊断潜力,而GNL没有显示出显著的相关性。结论:本研究首次提供了GC糖苷的综合表征,将少核桃苷n -聚糖与肿瘤侵袭性和不良临床结果联系起来。与已建立的临床生物标志物相比,这些聚糖表现出更好的预后表现。它们与MMP9的关联进一步表明在疾病进展中起关键作用。总之,这些发现表明,n -糖基化的改变,包括少糖糖化糖蛋白,有望在胃癌的未来预后和治疗应用中发挥作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Trimmed N-glycans define aggressive gastric cancer and predict clinical outcomes.

Rationale: Gastric cancer (GC) is a leading cause of cancer-related mortality, particularly in advanced stages where prognosis and targeted treatment remain challenging. The glycocalyx, a dense network of glycans and glycoproteins, is critical for tumor progression and immune evasion, yet its molecular signatures are poorly understood. This study investigates glycan-based biomarkers of aggressiveness, focusing on paucimannosidic N-glycans, a previously underexplored glycosylation pattern in cancer. Methods: High-throughput N-glycome analysis was performed on gastric tumors of varying aggressiveness, followed by Galanthus Nivalis Lectin (GNL) immunostaining to assess paucimannosidic glycans across tumor stages. Comparative analysis was performed against clinically relevant GC biomarkers (E-cadherin, p53, MSI, sTn, sLeA). TCGA analysis correlated key paucimannose-associated glycosyltransferases with clinical outcomes. Glycoproteomics identified glycoproteins carrying paucimannoses, later validated using immunoassays in tumor tissues for clinical relevance. Additionally, serum samples were analyzed to evaluate the non-invasive potential of GNL reactivity and associated glycoproteins. Results: Aggressive gastric tumors were significantly enriched in paucimannosidic N-glycans, a feature not previously reported in this malignancy. Lectin immunoblotting confirmed their disease specificity, with expression increasing with tumor progression. GNL staining outperformed established biomarkers in prognostic accuracy. TCGA analysis of more than 400 cases showed a strong correlation between high paucimannose-associated glycosyltransferase expression and poor prognosis. Glycoproteomics unexpectedly revealed paucimannose N-glycans primarily on intracellular ribosomal proteins, though key membrane proteins like MMP9 displayed aberrant paucimannosylation. MMP9 expression increased with tumor stage and grade, with tumors co-expressing MMP9 and paucimannosidic glycans exhibiting the worst prognosis. In serum, only MMP9 demonstrated diagnostic potential as a circulating biomarker, whereas GNL did not show a significant association. Conclusions: This study provides the first comprehensive characterization of the GC glycome, linking paucimannosidic N-glycans to tumor aggressiveness and poor clinical outcome. These glycans demonstrated superior prognostic performance compared to established clinical biomarkers. Their association with MMP9 further suggests a key role in disease progression. Together, these findings suggest that alterations in N-glycosylation, including paucimannosylated glycoproteins, hold promise for future prognostic and therapeutic applications in gastric cancer.

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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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