Biomarker discovery by plasma proteomics in familial Brugada Syndrome

Domenico, Marina Di; Scumaci, Domenica; Grasso, Simona; Gaspari, Marco; Curcio, Antonio; Oliva, Antonio; Ausania, Francesco; Nunzio, Ciro Di; Ricciardi, Carmela; Santini, Annamaria Chiara; Rizzo, Antonietta; Carratelli, Caterina Romano; Lamberti, Monica; Conti, David V.; Montagna, R; Tomei, C.; Malafoglia,; Vl, Pascali; Ricci, Pietrantonio; Indolfi, Ciro; Costanzo, Francesco; Cuda, Giovanni

doi:10.2741/4120

Cited by 19 publications

(8 citation statements)

References 17 publications

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“…Proteomic analysis and pathway analysis were performed according to previously published methods [ 56 – 58 ], see Supplementary File S1 for a detailed description.…”

Section: Methodsmentioning

confidence: 99%

Preclinical model in HCC: the SGK1 kinase inhibitor SI113 blocks tumor progressionin vitroandin vivoand synergizes with radiotherapy

et al. 2015

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The SGK1 kinase is pivotal in signal transduction pathways operating in cell transformation and tumor progression. Here, we characterize in depth a novel potent and selective pyrazolo[3,4-d]pyrimidine-based SGK1 inhibitor. This compound, named SI113, active in vitro in the sub-micromolar range, inhibits SGK1-dependent signaling in cell lines in a dose- and time-dependent manner. We recently showed that SI113 slows down tumor growth and induces cell death in colon carcinoma cells, when used in monotherapy or in combination with paclitaxel. We now demonstrate for the first time that SI113 inhibits tumour growth in hepatocarcinoma models in vitro and in vivo. SI113-dependent tumor inhibition is dose- and time-dependent. In vitro and in vivo SI113-dependent SGK1 inhibition determined a dramatic increase in apotosis/necrosis, inhibited cell proliferation and altered the cell cycle profile of treated cells. Proteome-wide biochemical studies confirmed that SI113 down-regulates the abundance of proteins downstream of SGK1 with established roles in neoplastic transformation, e.g. MDM2, NDRG1 and RAN network members. Consistent with knock-down and over-expressing cellular models for SGK1, SI113 potentiated and synergized with radiotherapy in tumor killing. No short-term toxicity was observed in treated animals during in vivo SI113 administration. These data show that direct SGK1 inhibition can be effective in hepatic cancer therapy, either alone or in combination with radiotherapy.

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“…Proteomic analysis and pathway analysis were performed according to previously published methods [ 56 – 58 ], see Supplementary File S1 for a detailed description.…”

Section: Methodsmentioning

confidence: 99%

Preclinical model in HCC: the SGK1 kinase inhibitor SI113 blocks tumor progressionin vitroandin vivoand synergizes with radiotherapy

et al. 2015

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“…In addition to cardiac, neural, digestive, and metabolic involvement, BrS may also affect other areas of the body. Potential biomarkers for BrS have been reportedly found in the serum or plasma of BrS patients (37,38), although the conclusions are disputed (39). Indeed, a multi-omics approach would be appropriate to study this syndrome, including not only genetics, but also epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and glycomics (28).…”

Section: Introductionmentioning

confidence: 99%

Brugada Syndrome: Warning of a Systemic Condition?

D'Imperio

Monasky

Micaglio

et al. 2021

Front. Cardiovasc. Med.

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Brugada syndrome (BrS) is a hereditary disorder, characterized by a specific electrocardiogram pattern and highly related to an increased risk of sudden cardiac death. BrS has been associated with other cardiac and non-cardiac pathologies, probably because of protein expression shared by the heart and other tissue types. In fact, the most commonly found mutated gene in BrS, SCN5A, is expressed throughout nearly the entire body. Consistent with this, large meals and alcohol consumption can trigger arrhythmic events in patients with BrS, suggesting a role for organs involved in the digestive and metabolic pathways. Ajmaline, a drug used to diagnose BrS, can have side effects on non-cardiac tissues, such as the liver, further supporting the idea of a role for organs involved in the digestive and metabolic pathways in BrS. The BrS electrocardiogram (ECG) sign has been associated with neural, digestive, and metabolic pathways, and potential biomarkers for BrS have been found in the serum or plasma. Here, we review the known associations between BrS and various organ systems, and demonstrate support for the hypothesis that BrS is not only a cardiac disorder, but rather a systemic one that affects virtually the whole body. Any time that the BrS ECG sign is found, it should be considered not a single disease, but rather the final step in any number of pathways that ultimately threaten the patient's life. A multi-omics approach would be appropriate to study this syndrome, including genetics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and glycomics, resulting eventually in a biomarker for BrS and the ability to diagnose this syndrome using a minimally invasive blood test, avoiding the risk associated with ajmaline testing.

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“…Second dimension separation was run on 10% SDS-polyacrylamide gels, (2W/gel; 25°C) until the bromophenol blue dye front reached the end of the gels [20]. Gels were stained with MS-compatible silver staining procedure [21–23]. Each pool analysis was performed in triplicate.…”

Section: Methodsmentioning

confidence: 99%

Plasma Proteomic Profiling in Hereditary Breast Cancer Reveals a BRCA1-Specific Signature: Diagnostic and Functional Implications

et al. 2015

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BackgroundBreast cancer (BC) is a leading cause of death among women. Among the major risk factors, an important role is played by familial history of BC. Germ-line mutations in BRCA1/2 genes account for most of the hereditary breast and/or ovarian cancers. Gene expression profiling studies have disclosed specific molecular signatures for BRCA1/2-related breast tumors as compared to sporadic cases, which might help diagnosis and clinical follow-up. Even though, a clear hallmark of BRCA1/2-positive BC is still lacking. Many diseases are correlated with quantitative changes of proteins in body fluids. Plasma potentially carries important information whose knowledge could help to improve early disease detection, prognosis, and response to therapeutic treatments. The aim of this study was to develop a comprehensive approach finalized to improve the recovery of specific biomarkers from plasma samples of subjects affected by hereditary BC.MethodsTo perform this analysis, we used samples from patients belonging to highly homogeneous population previously reported. Depletion of high abundant plasma proteins, 2D gel analysis, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis were used into an integrated approach to investigate tumor-specific changes in the plasma proteome of BC patients and healthy family members sharing the same BRCA1 gene founder mutation (5083del19), previously reported by our group, with the aim to identify specific signatures.ResultsThe comparative analysis of the experimental results led to the identification of gelsolin as the most promising biomarker.ConclusionsFurther analyses, performed using a panel of breast cancer cell lines, allowed us to further elucidate the signaling network that might modulate the expression of gelsolin in breast cancer.

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Biomarker discovery by plasma proteomics in familial Brugada Syndrome

Cited by 19 publications

References 17 publications

Preclinical model in HCC: the SGK1 kinase inhibitor SI113 blocks tumor progressionin vitroandin vivoand synergizes with radiotherapy

Preclinical model in HCC: the SGK1 kinase inhibitor SI113 blocks tumor progressionin vitroandin vivoand synergizes with radiotherapy

Brugada Syndrome: Warning of a Systemic Condition?

Plasma Proteomic Profiling in Hereditary Breast Cancer Reveals a BRCA1-Specific Signature: Diagnostic and Functional Implications

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