Molecular and pathobiological insights of bikunin/UTI in cancer

Lepedda, Antonio Junior; Nieddu, G.; Cannas, Claudia; Formato, Marilena

doi:10.1007/s11033-022-08117-2

Cited by 4 publications

(4 citation statements)

References 75 publications

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“…The latter is then modified by glycosylation in the Golgi apparatus and further linked to heavy chains through an ester bond with a non-sulfated N-acetylgalactosamine (GalNAc) residue of the chondroitin sulfate (CS) chain. This molecule is released into the plasma ( 24 ). A schematic describing the synthesis of AMBP encoded peptides is given in Supplementary Figure 12 .…”

Section: Discussionmentioning

confidence: 99%

“…Inflammatory conditions described significant modifications of the bikunin side chains regarding both sulfation and chain length composition of the CS moiety ( 34 ). Accordingly, free bikunin has been termed a novel acute phase protein ( 24 ). The inhibitory action of bikunin on endothelial cell layers is likely due to the interference with the calcium-dependent transforming growth factor-beta 1 signaling cascade ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

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Major endothelial damage markers identified from hemadsorption filters derived from treated patients with septic shock – endoplasmic reticulum stress and bikunin may play a role

Kasper,

Rodriguez-Alfonso,

Ständker

et al. 2024

Front. Immunol.

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IntroductionIn septic patients the damage of the endothelial barrier is decisive leading to circulatory septic shock with disseminated vascular coagulation, edema and multiorgan failure. Hemadsorption therapy leads to rapid resolution of clinical symptoms. We propose that the isolation of proteins adsorbed to hemadsorption devices contributes to the identification of mediators responsible for endothelial barrier dysfunction.Material and methodsPlasma materials enriched to hemadsorption filters (CytoSorb®) after therapy of patients in septic shock were fractionated and functionally characterized for their effect on cell integrity, viability, proliferation and ROS formation by human endothelial cells. Fractions were further studied for their contents of oxidized nucleic acids as well as peptides and proteins by mass spectrometry.ResultsIndividual fractions exhibited a strong effect on endothelial cell viability, the endothelial layer morphology, and ROS formation. Fractions with high amounts of DNA and oxidized DNA correlated with ROS formation in the target endothelium. In addition, defined proteins such as defensins (HNP-1), SAA1, CXCL7, and the peptide bikunin were linked to the strongest additive effects in endothelial damage.ConclusionOur results indicate that hemadsorption is efficient to transiently remove strong endothelial damage mediators from the blood of patients with septic shock, which explains a rapid clinical improvement of inflammation and endothelial function. The current work indicates that a combination of stressors leads to the most detrimental effects. Oxidized ssDNA, likely derived from mitochondria, SAA1, the chemokine CXCL7 and the human neutrophil peptide alpha-defensin 1 (HNP-1) were unique for their significant negative effect on endothelial cell viability. However, the strongest damage effect occurred, when, bikunin – cleaved off from alpha-1-microglobulin was present in high relative amounts (>65%) of protein contents in the most active fraction. Thus, a relevant combination of stressors appears to be removed by hemadsorption therapy which results in fulminant and rapid, though only transient, clinical restitution.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Major endothelial damage markers identified from hemadsorption filters derived from treated patients with septic shock – endoplasmic reticulum stress and bikunin may play a role

Kasper,

Rodriguez-Alfonso,

Ständker

et al. 2024

Front. Immunol.

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“…Bikunin, also known as the urinary trypsin inhibitor (UTI), is a glycoprotein in human plasma and urine, it has many biological functions and has been associated with many diseases, serum bikunin has been considered as the specific biomarkers of both congenital disorders of glycosylation and linkeropathies, 19 and may represent a non-invasive marker for early diagnosis of some life-threatening pathological conditions of pregnancy, 20 Lepedda et al analyzed bikunin expression in a variety of tumors by using UALCAN proteogenomic analysis portal, including ovarian cancer, breast cancer, colon cancer, lung adenocarcinoma, and so on, and discussed its inhibitory effects and mechanisms in cancer aggressiveness as well as its significance as cancer circulating biomarker. 21 Bikunin is one of the main anti-inflammatory mediators. It is upregulated in response to heme, reactive oxygen species (ROS) and to the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β.…”

Section: Discussionmentioning

confidence: 99%

Bikunin: A Promising Prognostic Biomarker for Acute-on-Chronic Liver Failure in Patients with Viral Hepatitis B

Qin,

Wang,

Zhang

et al. 2023

IDR

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Purpose To screen out potential prognostic biomarkers for HBV-related acute-on-chronic liver failure (HBV-ACLF). Patients and Methods Peripheral blood samples of HBV-ACLF patients (n=56) and normal controls (n=15) from the Affiliated Hospital of Southwest Medical University from January 2021 to April 2022 were collected, 5 normal patients and 10 patients with ACLF were randomly selected for Data independent acquisition (DIA) mass spectrometry analysis, and the potential core proteins were screened out via bioinformatics. All samples were validated by Enzyme linked immunosorbent assays (ELISA) technology, and the survival curve was constructed based on the patient’s 90-day survival time. Results A total of 247 differentially expressed proteins (DEPs) were screened, of which 148 were upregulated and 99 were down-regulated. The DEPs were mainly enriched in high-density lipoprotein particle remodeling, coagulation, and hemostasis and participated in signaling pathways such as cholesterol metabolism, coagulation cascades, and PPAR signaling pathway. Finally, bikunin was selected for further study and validated via the ELISA, compared with the normal group, bikunin was poorly expressed in the HBV-ACLF group, the difference was statistically significant (P < 0.0001), the area under the curve (AUC) for Receiver operating characteristic (ROC) analysis was 0.917. Furthermore, compared with the non-survival group, bikunin was highly expressed in the HBV-ACLF survival group, the difference was statistically significant (P=0.0015), and the survival curve showed a positive correlation with patient survival (P=0.0063). Conclusion The level of plasma bikunin in HBV-ACLF is down-regulated, which is positively correlated with the survival of the patients with HBV-ACLF, and is expected to become a new prognostic biomarker.

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“…The low expression of Alpha-1-Microglobulin/Bikunin Precursor ( AMBP ) has been reported to increase tumor progression in prostate cancer [ 36 ] and oral squamous carcinoma [ 37 ], but is relatively understudied in breast cancer. A study exploring expression of this gene across different cancers reported it to be downregulated in breast cancer [ 38 ]. However, this gene was found to be overexpressed in our positive margin cohort.…”

Section: Discussionmentioning

confidence: 99%

Association of clinicopathologic and molecular factors with the occurrence of positive margins in breast cancer

Praveen Kumar,

Vicente,

Liu

et al. 2023

Breast Cancer Res Treat

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Purpose To explore the association of clinicopathologic and molecular factors with the occurrence of positive margins after first surgery in breast cancer. Methods The clinical and RNA-Seq data for 951 (75 positive and 876 negative margins) primary breast cancer patients from The Cancer Genome Atlas (TCGA) were used. The role of each clinicopathologic factor for margin prediction and also their impact on survival were evaluated using logistic regression, Fisher’s exact test, and Cox proportional hazards regression models. In addition, differential expression analysis on a matched dataset (71 positive and 71 negative margins) was performed using Deseq2 and LASSO regression. Results Association studies showed that higher stage, larger tumor size (T), positive lymph nodes (N), and presence of distant metastasis (M) significantly contributed (p ≤ 0.05) to positive surgical margins. In case of surgery, lumpectomy was significantly associated with positive margin compared to mastectomy. Moreover, PAM50 Luminal A subtype had higher chance of positive margin resection compared to Basal-like subtype. Survival models demonstrated that positive margin status along with higher stage, higher TNM, and negative hormone receptor status was significant for disease progression. We also found that margin status might be a surrogate of tumor stage. In addition, 29 genes that could be potential positive margin predictors and 8 pathways were identified from molecular data analysis. Conclusion The occurrence of positive margins after surgery was associated with various clinical factors, similar to the findings reported in earlier studies. In addition, we found that the PAM50 intrinsic subtype Luminal A has more chance of obtaining positive margins compared to Basal type. As the first effort to pursue molecular understanding of the margin status, a gene panel of 29 genes including 17 protein-coding genes was also identified for potential prediction of the margin status which needs to be validated using a larger sample set.

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Molecular and pathobiological insights of bikunin/UTI in cancer

Cited by 4 publications

References 75 publications

Major endothelial damage markers identified from hemadsorption filters derived from treated patients with septic shock – endoplasmic reticulum stress and bikunin may play a role

Major endothelial damage markers identified from hemadsorption filters derived from treated patients with septic shock – endoplasmic reticulum stress and bikunin may play a role

Bikunin: A Promising Prognostic Biomarker for Acute-on-Chronic Liver Failure in Patients with Viral Hepatitis B

Association of clinicopathologic and molecular factors with the occurrence of positive margins in breast cancer

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