Multi-omics Biomarker Pipeline Reveals Elevated Levels of Protein-glutamine Gamma-glutamyltransferase 4 in Seminal Plasma of Prostate Cancer Patients

Drabovich, Andrei P.; Saraon, Punit; Drabovich, Mikalai; Karakosta, Theano D.; Dimitromanolakis, Apostolos; Hyndman, M. Eric; Jarvi, Keith; Diamandis, Eleftherios P.

doi:10.1074/mcp.ra119.001612

Cited by 33 publications

(44 citation statements)

References 72 publications

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“…Men with varicocele were identified to have altered seminal plasma proteins, including peroxiredoxin 2, fatty acid synthase, and fibronectin 1 (14,15). Seminal transglutaminase 4, which is predominantly expressed in the prostate gland, was found to be associated with prostate cancer (16). Spermatozoa structure components may also present in the seminal plasma and are therefore regarded as signals of spermatozoa morphology and physiological state (9).…”

Section: Introductionmentioning

confidence: 99%

Seminal Plasma Proteome as an Indicator of Sperm Dysfunction and Low Sperm Motility in Chickens

Li¹,

Sun²,

Ni³

et al. 2020

Molecular & Cellular Proteomics

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Molecular mechanisms underlying sperm motility have not been fully explained, particularly in chickens. The objective was to identify seminal plasma proteins associated with chicken sperm motility by comparing the seminal plasma proteomic profile of roosters with low sperm motility (LSM, n = 4) and high sperm motility (HSM, n = 4). Using a label-free MS-based method, a total of 522 seminal plasma proteins were identified, including 386 (∼74%) previously reported and 136 novel ones. A total of 70 differentially abundant proteins were defined, including 48 more-abundant, 15 less-abundant, and seven proteins unique to the LSM group (specific proteins). Key secretory proteins like less-abundant adhesion G-protein coupled receptor G2 (ADGRG2) and more-abundant serine peptidase inhibitor Kazal-type 2 (SPINK2) in the LSM suggested that the corresponding secretory tissues played a crucial role in maintaining sperm motility. Majority (80%) of the more-abundant and five specific proteins were annotated to the cytoplasmic domain which might be a result of higher plasma membrane damage and acrosome dysfunction in LSM. Additionally, more-abundant mitochondrial proteins were detected in LSM seminal plasma associated with lower spermatozoa mitochondrial membrane potential (ΔΨm) and ATP concentrations. Further studies showed that the spermatozoa might be suffering from oxidative stress, as the amount of spermatozoa reactive oxygen species (ROS) were largely enhanced, seminal malondialdehyde (MDA) concentrations were increased, and the seminal plasma total antioxidant capacity (T-AOC) were decreased. Our study provides an additional catalogue of chicken seminal plasma proteome and supports the idea that seminal plasma could be as an indicator of spermatozoa physiology. More-abundant of acrosome, mitochondria and sperm cytoskeleton proteins in the seminal plasma could be a marker of sperm dysfunction and loss of motility. The degeneration of spermatozoa caused by the reduced seminal T-AOC and enhanced oxidative stress might be potential determinants of low sperm motility. These results could extend our understanding of sperm motility and sperm physiology regulation.

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Section: Introductionmentioning

confidence: 99%

Seminal Plasma Proteome as an Indicator of Sperm Dysfunction and Low Sperm Motility in Chickens

Li¹,

Sun²,

Ni³

et al. 2020

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

show abstract

“…Recursive feature elimination was exploited to select subsets of expressed genes and methylation data to classify breast cancer disease subtypes with a Random Forest ( 3 ). Genes prioritization allowed prognosis prediction in different cancer types from epigenomics, transcriptomics, and genomics data ( 38 ), and biomarker discovery in prostate cancer ( 28 ). In ( 39 ) authors weight gene-gene interaction from transcriptomics and genomics data with a random walked-based method to select the most important interaction for survival prediction in breast cancer and neuroblastoma patients.…”

Section: Resultsmentioning

confidence: 99%

Integrated Multi-Omics Analyses in Oncology: A Review of Machine Learning Methods and Tools

et al. 2020

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In recent years, high-throughput sequencing technologies provide unprecedented opportunity to depict cancer samples at multiple molecular levels. The integration and analysis of these multi-omics datasets is a crucial and critical step to gain actionable knowledge in a precision medicine framework. This paper explores recent data-driven methodologies that have been developed and applied to respond major challenges of stratified medicine in oncology, including patients' phenotyping, biomarker discovery, and drug repurposing. We systematically retrieved peer-reviewed journals published from 2014 to 2019, select and thoroughly describe the tools presenting the most promising innovations regarding the integration of heterogeneous data, the machine learning methodologies that successfully tackled the complexity of multi-omics data, and the frameworks to deliver actionable results for clinical practice. The review is organized according to the applied methods: Deep learning, Network-based methods, Clustering, Features Extraction, and Transformation, Factorization. We provide an overview of the tools available in each methodological group and underline the relationship among the different categories. Our analysis revealed how multi-omics datasets could be exploited to drive precision oncology, but also current limitations in the development of multi-omics data integration.

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Section: Discussionmentioning

confidence: 99%

“…During the past decade, the proteomics platform was used to profile the proteins in seminal fluids of patients diagnosed with several types of cancers, such as prostate cancer [25][26][27], testicular cancer [21,22,28], Hodgkin's disease [23], and leukemia [24]. Based on their ability to detect the expression of thousands of proteins simultaneously, proteomics techniques are of great interest to unravel the molecular mechanisms leading to infertility in cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of Key Proteins Associated with Sperm Motility and Fertility Potential in Cancer Patients

Selvam

Finelli

Baskaran

et al. 2020

IJMS

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Cancer has adverse effects on male reproductive health. Conventional semen analysis does not explain the molecular changes in the spermatozoa of cancer patients. Currently, proteomics is being widely used to identify the fertility-associated molecular pathways affected in spermatozoa. The objective of this study was to evaluate the sperm proteome of patients with various types of cancer. Cryopreserved semen samples from patients (testicular cancer, n = 40; Hodgkin’s disease, n = 32; lymphoma, n = 20; leukemia, n = 17) before starting therapy were used for proteomic analysis, while samples from fertile donors (n = 19) were included as controls. The proteomic profiling of sperm was carried out by liquid chromatography-tandem mass spectrometry, and differentially expressed proteins involved in the reproductive processes were validated by Western blotting. Bioinformatic analysis revealed that proteins associated with mitochondrial dysfunction, oxidative phosphorylation, and Sirtuin signaling pathways were dysregulated in cancer patients, while oxidative phosphorylation and tricarboxylic acid cycle were predicted to be deactivated. Furthermore, the analysis revealed dysregulation of key proteins associated with sperm fertility potential and motility (NADH:Ubiquinone oxidoreductase core subunit S1, superoxide dismutase 1, SERPINA5, and cytochrome b-c1 complex subunit 2) in the cancer group, which were further validated by Western blot. Dysfunctional molecular mechanisms essential for fertility in cancer patients prior to therapy highlight the potential impact of cancer phenotype on male fertility.

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Multi-omics Biomarker Pipeline Reveals Elevated Levels of Protein-glutamine Gamma-glutamyltransferase 4 in Seminal Plasma of Prostate Cancer Patients

Cited by 33 publications

References 72 publications

Seminal Plasma Proteome as an Indicator of Sperm Dysfunction and Low Sperm Motility in Chickens

Seminal Plasma Proteome as an Indicator of Sperm Dysfunction and Low Sperm Motility in Chickens

Integrated Multi-Omics Analyses in Oncology: A Review of Machine Learning Methods and Tools

Dysregulation of Key Proteins Associated with Sperm Motility and Fertility Potential in Cancer Patients

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