Clear-cell renal cell carcinoma (ccRCC) presents challenges to clinical management because of late-stage detection, treatment resistance, and frequent disease recurrence. Metabolically, ccRCC has a well-described Warburg effect utilization of glucose, but how this affects complex carbohydrate synthesis and alterations to protein and cell surface glycosylation is poorly defined. Using an imaging mass spectrometry approach, N-glycosylation patterns and compositional differences were assessed between tumor and nontumor regions of formalin-fixed clinical ccRCC specimens and tissue microarrays. Regions of normal kidney tissue samples were also evaluated for N-linked glycan-based distinctions between cortex, medullar, glomeruli, and proximal tubule features. Most notable was the proximal tubule localized detection of abundant multiantennary N-glycans with bisecting N-acetylglucosamine and multziple fucose residues. These glycans are absent in ccRCC tissues, while multiple tumor-specific N-glycans were detected with tri- and tetra-antennary structures and varying levels of fucosylation and sialylation. A polycystic kidney disease tissue was also characterized for N-glycan composition, with specific nonfucosylated glycans detected in the cyst fluid regions. Complementary to the imaging mass spectrometry analyses was an assessment of transcriptomic gene array data focused on the fucosyltransferase gene family and other glycosyltransferase genes. The transcript levels of the FUT3 and FUT6 genes responsible for the enzymes that add fucose to N-glycan antennae were significantly decreased in all ccRCC tissues relative to matching nontumor tissues. These striking differences in glycosylation associated with ccRCC could lead to new mechanistic insight into the glycobiology underpinning kidney malignancies and suggest the potential for new therapeutic interventions and diagnostic markers.

中文翻译：

---

使用MALDI成像质谱仪定义正常和癌症组织中的人肾脏N-糖基。

透明细胞肾细胞癌（ccRCC）由于后期检测，治疗耐药性和频繁的疾病复发而对临床管理提出了挑战。代谢上，ccRCC具有充分描述的葡萄糖的Warburg效应利用，但如何影响复杂的碳水化合物合成以及对蛋白质和细胞表面糖基化的改变却知之甚少。使用成像质谱方法，对福尔马林固定的临床ccRCC标本和组织微阵列的肿瘤和非肿瘤区域之间的N-糖基化模式和组成差异进行了评估。还评估了正常肾脏组织样本区域的皮质，髓质，肾小球和近端小管特征之间基于N联聚糖的区别。最值得注意的是近端小管局部检测了富含二等分N-乙酰氨基葡萄糖和多链岩藻糖残基的多天线N-聚糖。ccRCC组织中不存在这些聚糖，而检测到具有三天线和四天线结构以及岩藻糖基化和唾液酸化水平不同的多种肿瘤特异性N聚糖。多囊性肾脏疾病组织也具有N-聚糖成分的特征，在囊液区域中检测到特定的非岩藻糖基化聚糖。对成像质谱分析的补充是对侧链岩藻糖基转移酶基因家族和其他糖基转移酶基因的转录组基因阵列数据的评估。相对于匹配的非肿瘤组织，负责将岩藻糖添加到N-聚糖触角的酶的FUT3和FUT6基因的转录水平在所有ccRCC组织中均显着降低。与ccRCC相关的糖基化方面的这些显着差异可能会导致对支持肾脏恶性肿瘤的糖生物学的新机制的了解，并为新的治疗干预措施和诊断标记物提供了潜力。