精密 N-糖蛋白组学显示 LacdiNAc 升高是肝内胆管癌的新特征,Molecular Oncology

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精密 N-糖蛋白组学显示 LacdiNAc 升高是肝内胆管癌的新特征
Molecular Oncology ( IF 5.0 ) Pub Date : 2021-12-02 , DOI: 10.1002/1878-0261.13147
Jun Li ₁ , Ting Zhao ₁ , Jing Li ₁ , Jiechen Shen ₁ , Li Jia ₁ , Bojing Zhu ₁ , Liuyi Dang ₁ , Chen Ma ₁ , Didi Liu ₁ , Fan Mu ₂ , Liangshuo Hu ₂ , Shisheng Sun ₁

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原发性肝癌，主要包括肝细胞癌（HCC）和肝内胆管癌（ICC），仍然是一个主要的全球健康问题。尽管 ICC 在临床上与 HCC 不同，但它们的分子差异仍不清楚。在这项研究中，对 ICC 和 HCC 肿瘤以及癌旁组织进行了精确的 N-糖蛋白质组学分析，以研究它们异常的位点特异性 N-糖基化。通过使用我们新开发的糖蛋白组学方法和称为“StrucGP”的新算法，从 ICC 和 HCC 肿瘤中的 894 个糖蛋白中鉴定出总共 486 个连接在 1235 个糖位点上的 N-聚糖结构。值得注意的是，具有不常见的 LacdiNAc (GalNAcβ1-4GlcNAc) 结构的聚糖与其异构聚糖不同。除了在 ICC 和 HCC 中通常升高的几种双触角和/或二等分聚糖外，一些含有 LacdiNAc、三触角和核心岩藻糖基化的聚糖在 ICC 中独特地增加。更有趣的是，几乎所有含 LacdiNAc 的 N-糖肽在 ICC 肿瘤中均增强，但在 HCC 肿瘤中没有增强，这一现象进一步通过凝集素组织化学和 ICC 中 β1-4 GalNAc 转移酶在 mRNA 和蛋白质表达水平的高表达得到证实. 在 ICC 中独特检测到的新型 N-聚糖改变为未来有关发现 ICC 诊断生物标志物、治疗靶点和机制研究的研究提供了宝贵的资源。几乎所有含 LacdiNAc 的 N-糖肽在 ICC 肿瘤中均增强，但在 HCC 肿瘤中未增强，这一现象通过凝集素组织化学和 ICC 中 mRNA 和蛋白质表达水平的 β1-4 GalNAc 转移酶的高表达进一步证实。在 ICC 中唯一检测到的新型 N-聚糖改变为未来有关发现 ICC 诊断生物标志物、治疗靶点和机制研究的研究提供了宝贵的资源。几乎所有含 LacdiNAc 的 N-糖肽在 ICC 肿瘤中均增强，但在 HCC 肿瘤中未增强，这一现象通过凝集素组织化学和 ICC 中 mRNA 和蛋白质表达水平的 β1-4 GalNAc 转移酶的高表达进一步证实。在 ICC 中唯一检测到的新型 N-聚糖改变为未来有关发现 ICC 诊断生物标志物、治疗靶点和机制研究的研究提供了宝贵的资源。

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Precision N-glycoproteomics reveals elevated LacdiNAc as a novel signature of intrahepatic cholangiocarcinoma

Primary liver cancer, mainly comprising hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), remains a major global health problem. Although ICC is clinically different from HCC, their molecular differences are still largely unclear. In this study, precision N-glycoproteomic analysis was performed on both ICC and HCC tumors as well as paracancer tissues to investigate their aberrant site-specific N-glycosylation. By using our newly developed glycoproteomic methods and novel algorithm, termed ‘StrucGP’, a total of 486 N-glycan structures attached on 1235 glycosites were identified from 894 glycoproteins in ICC and HCC tumors. Notably, glycans with uncommon LacdiNAc (GalNAcβ1-4GlcNAc) structures were distinguished from their isomeric glycans. In addition to several bi-antennary and/or bisecting glycans that were commonly elevated in ICC and HCC, a number of LacdiNAc-containing, tri-antennary, and core-fucosylated glycans were uniquely increased in ICC. More interestingly, almost all LacdiNAc-containing N-glycopeptides were enhanced in ICC tumor but not in HCC tumor, and this phenomenon was further confirmed by lectin histochemistry and the high expression of β1-4 GalNAc transferases in ICC at both mRNA and protein expression levels. The novel N-glycan alterations uniquely detected in ICC provide a valuable resource for future studies regarding to the discovery of ICC diagnostic biomarkers, therapeutic targets, and mechanism investigations.

更新日期：2021-12-02

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