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. 2015 Nov 6;14(11):4538-49.
doi: 10.1021/acs.jproteome.5b00255. Epub 2015 Sep 30.

Differential N-Glycosylation Patterns in Lung Adenocarcinoma Tissue

L Renee Ruhaak, Sandra L Taylor, Carol Stroble  1 , Uyen Thao Nguyen, Evan A Parker, Ting Song, Carlito B Lebrilla, William N Rom  2 , Harvey Pass  3 , Kyoungmi Kim, Karen Kelly  1 , Suzanne Miyamoto  1
Affiliations

Differential N-Glycosylation Patterns in Lung Adenocarcinoma Tissue

L Renee Ruhaak et al. J Proteome Res. .

Abstract

To decrease the mortality of lung cancer, better screening and diagnostic tools as well as treatment options are needed. Protein glycosylation is one of the major post-translational modifications that is altered in cancer, but it is not exactly clear which glycan structures are affected. A better understanding of the glycan structures that are differentially regulated in lung tumor tissue is highly desirable and will allow us to gain greater insight into the underlying biological mechanisms of aberrant glycosylation in lung cancer. Here, we assess differential glycosylation patterns of lung tumor tissue and nonmalignant tissue at the level of individual glycan structures using nLC-chip-TOF-MS. Using tissue samples from 42 lung adenocarcinoma patients, 29 differentially expressed (FDR < 0.05) glycan structures were identified. The levels of several oligomannose type glycans were upregulated in tumor tissue. Furthermore, levels of fully galactosylated glycans, some of which were of the hybrid type and mostly without fucose, were decreased in cancerous tissue, whereas levels of non- or low-galactosylated glycans mostly with fucose were increased. To further assess the regulation of the altered glycosylation, the glycomics data was compared to publicly available gene expression data from lung adenocarcinoma tissue compared to nonmalignant lung tissue. The results are consistent with the possibility that the observed N-glycan changes have their origin in differentially expressed glycosyltransferases. These results will be used as a starting point for the further development of clinical glycan applications in the fields of imaging, drug targeting, and biomarkers for lung cancer.

Keywords: N-Glycosylation; NSCLC; gene expression; nLC−MS profiling; tissue.

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Figures

Figure 1
Figure 1
Lung adenocarcinoma tissues can be separated from the nonmalignant tissue from the same individual based on their N-glycosylation pattern. Score plots of the PLS-LDA analysis are shown for (A) unreduced glycan compositions, (B) reduced glycan compositions, and (C) N-glycan structures. Using leave-one-out cross-validation, accurate classification rates were calculated to be 79.5% for the unreduced glycan compositions using 3 latent components, 82.0% for the reduced glycan compositions using 4 latent components, and 82.0 for the N-glycan structures using 3 latent components.
Figure 2
Figure 2
Differential expression of glycan compositions in lung adenocarcinoma tissue compared to controls. Putative structures are shown for the glycans that are present at significantly different (FDR < 0.05) levels in the unreduced analysis. Glycans of which the levels are decreased in malignant tissue are shown on the left, whereas glycans of which the levels are increased in malignant tissue are shown on the right. Symbol key: blue square is N-acetylglucosamine, green ball is mannose, yellow ball is galactose, red triangle is fucose, and purple diamond is N-acetylneuraminic acid.
Figure 3
Figure 3
PGC–LC–MS chromatogram of reduced glycans from a malignant lung tissue sample. The extracted glycan chromatogram (chromatogram of all glycans summed) is shown in black, whereas extracted ion chromatograms of individual glycans are shown in color. The chromatograms have been annotated with actual structures, as obtained by comparing the retention times to our in-house built serum N-glycan library. For symbol key, see Figure 2.
Figure 4
Figure 4
Schematic overview of N-glycan processing catalyzed by carbohydrate acting enzymes in the Golgi. Enzymes involved in glycan processing have been included, but sugar nucleotide donors have not been included in this figure. For symbol key, see Figure 2.
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