Unfolding the cascade of SERPINA3: Inflammation to cancer

Soman, Anjana; Nair, S. Asha

doi:10.1016/j.bbcan.2022.188760

Cited by 25 publications

(22 citation statements)

References 145 publications

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“…SERPINA3 has been reported to principally works as an inhibitor in maintaining cellular homeostasis; it is a matricellular acute-phase glycoprotein that appears to be the sole nuclear-binding secretory serpin [ 22 ]. Several studies have emerged in recent years demonstrating its link to cancer biology [ 23 , 24 , 25 , 26 ].…”

Section: Resultsmentioning

confidence: 99%

High Throughput Isolation and Data Independent Acquisition Mass Spectrometry (DIA-MS) of Urinary Extracellular Vesicles to Improve Prostate Cancer Diagnosis

Zhang

et al. 2022

Molecules

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Proteomic profiling of extracellular vesicles (EVs) represents a promising approach for early detection and therapeutic monitoring of diseases such as cancer. The focus of this study was to apply robust EV isolation and subsequent data-independent acquisition mass spectrometry (DIA-MS) for urinary EV proteomics of prostate cancer and prostate inflammation patients. Urinary EVs were isolated by functionalized magnetic beads through chemical affinity on an automatic station, and EV proteins were analyzed by integrating three library-base analyses (Direct-DIA, GPF-DIA, and Fractionated DDA-base DIA) to improve the coverage and quantitation. We assessed the levels of urinary EV-associated proteins based on 40 samples consisting of 20 cases and 20 controls, where 18 EV proteins were identified to be differentiated in prostate cancer outcome, of which three (i.e., SERPINA3, LRG1, and SCGB3A1) were shown to be consistently upregulated. We also observed 6 out of the 18 (33%) EV proteins that had been developed as drug targets, while some of them showed protein-protein interactions. Moreover, the potential mechanistic pathways of 18 significantly different EV proteins were enriched in metabolic, immune, and inflammatory activities. These results showed consistency in an independent cohort with 20 participants. Using a random forest algorithm for classification assessment, including the identified EV proteins, we found that SERPINA3, LRG1, or SCGB3A1 add predictable value in addition to age, prostate size, body mass index (BMI), and prostate-specific antigen (PSA). In summary, the current study demonstrates a translational workflow to identify EV proteins as molecular markers to improve the clinical diagnosis of prostate cancer.

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Section: Resultsmentioning

confidence: 99%

High Throughput Isolation and Data Independent Acquisition Mass Spectrometry (DIA-MS) of Urinary Extracellular Vesicles to Improve Prostate Cancer Diagnosis

Zhang

et al. 2022

Molecules

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“…SERPINA3, or alpha-1-antichymotrypsin, is a member of the serine-protease inhibitor (SERPIN) superfamily. SERPINA3 is a highly glycosylated protein with a molecular wight of roughly 46kDa ( 41 ). SERPINA3 is an acute-phase protein that is mainly synthesized in the liver and secreted into the plasma.…”

Section: Discussionmentioning

confidence: 99%

“…SERPINA3 is an acute-phase protein that is mainly synthesized in the liver and secreted into the plasma. Altered expression of SERPINA3 in plasma, organs, cerebrospinal fluid, and urine is reportedly associated with various inflammatory diseases and cancers ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

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Urinary proteome profiles associated with cognitive decline in community elderly residents—A pilot study

et al. 2023

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Non-invasive and simple methods enabling easy identification of individuals at high risk of cognitive decline are needed as preventive measures against dementia. This pilot study aimed to explore protein biomarkers that can predict cognitive decline using urine, which can be collected non-invasively. Study subjects were selected from participants in a cohort study of middle-aged and older community-dwelling adults who underwent cognitive testing using the Mini-Mental State Examination and provided spot urine samples at two time points with an interval of approximately 5 years. Seven participants whose cognitive function declined 4 or more points from baseline (Group D) and 7 sex- and age-matched participants whose cognitive function remained within the normal range during the same period (Group M) were selected. Urinary proteomics using mass spectrometry was performed and discriminant models were created using orthogonal partial least squares-discriminant analysis (OPLS-DA). OPLS-DA yielded two models that significantly discriminated between the two groups at baseline and follow-up. Both models had ORM1, ORM2, and SERPINA3 in common. A further OPLS-DA model using baseline ORM1, ORM2, and SERPINA3 data showed similar predictive performance for data at follow-up as it did for baseline data (sensitivity: 0.85, specificity: 0.85), with the receiver operating characteristic curve analysis yielding an area under the curve of 0.878. This prospective study demonstrated the potential for using urine to identify biomarkers of cognitive decline.

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“…As a secretory protein, Serpina3n/SERPINA3 is translocated from ribosomes into the rough endoplasmic reticulum, where it undergoes appropriate folding before being secreted into the extracellular space 16 . The promoter and enhancer regions of Serpina3n/SERPINA3 genes harbour binding sites for nuclear factor kappa B (NF‐kB), 17,18 signal transducer and activator of transcription (STAT), 19 activator protein‐1 (AP1), 20 nuclear factor‐1‐X (NFIX), 21 nuclear orphan receptor Nur77, 22 responsive elements for cytokines oncostatin M, tumour necrosis factor α (TNFa) and Interleukin 1 (IL1) 23 . The binding sites and responsive elements provide the structural basis for its capability of rapid responses to inflammation in many cell types.…”

Section: Serpina3n/serpina3's Molecular Structure Determines Its Uniq...mentioning

confidence: 99%

Regulation of CNS pathology by Serpina3n/SERPINA3: The knowns and the puzzles

Zhu,

Lan,

Park

et al. 2024

Neuropathology Appl Neurobio

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Neuroinflammation, blood–brain barrier (BBB) dysfunction, neuron and glia injury/death and myelin damage are common central nervous system (CNS) pathologies observed in various neurological diseases and injuries. Serine protease inhibitor (Serpin) clade A member 3n (Serpina3n), and its human orthologue SERPINA3, is an acute‐phase inflammatory glycoprotein secreted primarily by the liver into the bloodstream in response to systemic inflammation. Clinically, SERPINA3 is dysregulated in brain cells, cerebrospinal fluid and plasma in various neurological conditions. Although it has been widely accepted that Serpina3n/SERPINA3 is a reliable biomarker of reactive astrocytes in diseased CNS, recent data have challenged this well‐cited concept, suggesting instead that oligodendrocytes and neurons are the primary sources of Serpina3n/SERPINA3. The debate continues regarding whether Serpina3n/SERPINA3 induction represents a pathogenic or a protective mechanism. Here, we propose possible interpretations for previously controversial data and present perspectives regarding the potential role of Serpina3n/SERPINA3 in CNS pathologies, including demyelinating disorders where oligodendrocytes are the primary targets. We hypothesise that the ‘good’ or ‘bad’ aspects of Serpina3n/SERPINA3 depend on its cellular sources, its subcellular distribution (or mis‐localisation) and/or disease/injury types. Furthermore, circulating Serpina3n/SERPINA3 may cross the BBB to impact CNS pathologies. Cell‐specific genetic tools are critically important to tease out the potential roles of cell type‐dependent Serpina3n in CNS diseases/injuries.

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Unfolding the cascade of SERPINA3: Inflammation to cancer

Cited by 25 publications

References 145 publications

High Throughput Isolation and Data Independent Acquisition Mass Spectrometry (DIA-MS) of Urinary Extracellular Vesicles to Improve Prostate Cancer Diagnosis

High Throughput Isolation and Data Independent Acquisition Mass Spectrometry (DIA-MS) of Urinary Extracellular Vesicles to Improve Prostate Cancer Diagnosis

Urinary proteome profiles associated with cognitive decline in community elderly residents—A pilot study

Regulation of CNS pathology by Serpina3n/SERPINA3: The knowns and the puzzles

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