Abstract
Currently prostate-specific antigen is used for prostate cancer (PCa) screening, however it lacks the necessary specificity for differentiating PCa from other diseases of the prostate such as benign prostatic hyperplasia (BPH), presenting a clinical need to distinguish these cases at the molecular level. Protein glycosylation plays an important role in a number of cellular processes involved in neoplastic progression and is aberrant in PCa. In this study, we systematically interrogate the alterations in the circulating levels of hundreds of serum proteins and their glycoforms in PCa and BPH samples using multi-lectin affinity chromatography and quantitative mass spectrometry-based proteomics. Specific lectins (AAL, PHA-L and PHA-E) were used to target and chromatographically separate core-fucosylated and highly-branched protein glycoforms for analysis, as differential expression of these glycan types have been previously associated with PCa. Global levels of CD5L, CFP, C8A, BST1, and C7 were significantly increased in the PCa samples. Notable glycoform-specific alterations between BPH and PCa were identified among proteins CD163, C4A, and ATRN in the PHA-L/E fraction and among C4BPB and AZGP1 glycoforms in the AAL fraction. Despite these modest differences, substantial similarities in glycoproteomic profiles were observed between PCa and BPH sera.
Highlights
Prostate-specific antigen is used for prostate cancer (PCa) screening, it lacks the necessary specificity for differentiating PCa from other diseases of the prostate such as benign prostatic hyperplasia (BPH), presenting a clinical need to distinguish these cases at the molecular level
Three separate fractions were collected from the multi-lectin affinity chromatography (M-LAC) column including the flow-through of unbound proteins (UNB fraction), proteins bound to aurantia lectin (AAL) (AAL fraction), and proteins bound to Phaseolus vulgaris erythroagglutinin (PHA-L/E) (PHA fraction)
We observed alterations in circulating levels of proteins both at the global level and among specific glycoforms captured by lectins with affinity for core-fucosylated species (AAL) and highly branched complex-type glycans (PHA-L/E)
Summary
Prostate-specific antigen is used for prostate cancer (PCa) screening, it lacks the necessary specificity for differentiating PCa from other diseases of the prostate such as benign prostatic hyperplasia (BPH), presenting a clinical need to distinguish these cases at the molecular level. The bulk of the research on glycosylation changes in prostate cancer has focused on characterizing the various glycoforms of PSA to improve its clinical utility[19,20,21,22,23] These studies find that core-fucosylation and the sialic acid linkage of PSA glycoforms play a key role in differentiating non-PCa patients and those with BPH from low- and high-risk PCa cases. We chose Aleuria aurantia lectin (AAL) to capture core-fucosylated proteins and Phaseolus vulgaris leucoagglutinin erythroagglutinin, and Phaseolus vulgaris erythroagglutinin (jointly abbreviated as PHA-L/E) to capture highly branched glycans[25] These lectins were chosen to target types of glycosylation reported to be aberrant in prostate cancer, while simultaneously fractionating the complex mixture of proteins to enhance depth of analysis. We identify differences at the global protein level as well as among specific glycoforms of quantitated proteins that could be used to aid in differentiating BPH from PCa cases
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