Multi-omics evaluation of the prognostic value and immune signature of FCN1 in pan-cancer and its relationship with proliferation and apoptosis in acute myeloid leukemia.

Background: The FCN1 gene encodes the ficolin-1 protein, implicated in the pathogenesis of various diseases, though its precise role in tumorigenesis remains elusive. This study aims to elucidate the prognostic significance, immune signature, and treatment response associated with FCN1 across diverse cancer types. Methods: Employing multi-omics data, we conducted a comprehensive assessment, encompassing tissue-specific and single-cell-specific expression disparities, pan-cancer expression patterns, epigenetic modifications affecting FCN1 expression, and the immune microenvironment. Our investigation primarily focused on the clinical prognostic attributes, immune profiles, potential molecular mechanisms, and candidate therapeutic agents concerning FCN1 and acute myeloid leukemia (AML). Additionally, in vitro experiments were performed to scrutinize the impact of FCN1 knockdown on cell proliferation, apoptosis, and cell cycle dynamics within the AML cell line U937 and NB4. Results: FCN1 expression exhibits widespread dysregulation across various cancers. Through both univariate and multivariate Cox regression analyses, FCN1 has been identified as an independent prognostic indicator for AML. Immunological investigations elucidate FCN1's involvement in modulating inflammatory responses within the tumor microenvironment and its correlation with treatment efficacy. Remarkably, the deletion of FCN1 influences the proliferation, apoptosis, and cell cycle dynamics of U937 cells and NB4 cells. Conclusion: These findings underscore FCN1 as a promising pan-cancer biomarker indicative of macrophage infiltration, intimately linked with the tumor microenvironment and treatment responsiveness, and pivotal for cellular mechanisms within AML cell lines.

The Soluble Lectin Families as Novel Biomarkers for COVID-19 Pneumonia.

BACKGROUND/AIM: The lung-specific soluble lectins, SP-A and SP-D have been clinically used to diagnose interstitial lung disease, but their clinical significance in COVID-19 remains controversial. This study was undertaken to determine their association with other lectins (MBL and FCN1), disease severity, and radiographs in COVID-19 patients. PATIENTS AND METHODS: A total of 131 patients with COVID-19 admitted in the Sapporo Medical University Hospital between May 22 and September 19, 2021, were enrolled in the study. Data including demographics, medical history, symptoms, signs, laboratory findings, and radiological images were collected from the patients' medical records. Chest computed tomography (CT) scanning was performed at admission. Serum levels of surfactant protein A and D (SP-A and SP-D), mannose-binding lectin (MBL) and ficolin1 (FCN1) were measured using enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: Compared to the control group, the COVID-19 group had significantly higher serum SP-A and FCN1 levels on admission (SP-A: 59.60±38.89 vs. 35.61±11.22 ng/ml; p<0.01, FCN1: 542.45±506.04 vs. 250.6±161.1 ng/ml; p<0.01). The severe group in COVID-19 had significantly higher serum SP-D and lower MBL levels than the non-severe group (SP-D: 141.7±155.7 vs. 61.41±54.54 ng/ml; p<0.01, MBL: 1,670±1,240 vs. 2,170±1,140 ng/ml; p<0.05). SP-D strongly reflected the degree of imaging findings, whereas SP-A showed a significant correlation, albeit slightly weaker than SP-D. Conversely, MBL and FNC1 were not significantly correlated with imaging findings. CONCLUSION: Among soluble serum lectins, SP-A and SP-D may be more sensitive to CT findings than reported disease biomarkers such as IL-6, LDH, and CRP due to their lung-specific characteristics.

Identification of FCN1 as a novel macrophage infiltration-associated biomarker for diagnosis of pediatric inflammatory bowel diseases.

BACKGROUND: The incidence of pediatric inflammatory bowel disease (PIBD) has been steadily increasing globally. Delayed diagnosis of PIBD increases the risk of complications and contributes to growth retardation. To improve long-term outcomes, there is a pressing need to identify novel markers for early diagnosis of PIBD. METHODS: The candidate biomarkers for PIBD were identified from the GSE117993 dataset by two machine learning algorithms, namely LASSO and mSVM-RFE, and externally validated in the GSE126124 dataset and our PIBD cohort. The role of ficolin-1 (FCN1) in PIBD and its association with macrophage infiltration was investigated using the CIBERSORT method and enrichment analysis of the single-cell dataset GSE121380, and further validated using immunoblotting, qRT-PCR, and immunostaining in colon biopsies from PIBD patients, a juvenile murine DSS-induced colitis model, and THP-1-derived macrophages. RESULTS: FCN1 showed great diagnostic performance for PIBD in an independent clinical cohort with the AUC of 0.986. FCN1 expression was upregulated in both colorectal biopsies and blood samples from PIBD patients. Functionally, FCN1 was associated with immune-related processes in the colonic mucosa of PIBD patients, and correlated with increased proinflammatory M1 macrophage infiltration. Furthermore, single-cell transcriptome analysis and immunostaining revealed that FCN1 was almost exclusively expressed in macrophages infiltrating the colonic mucosa of PIBD patients, and these FCN1+ macrophages were related to hyper-inflammation. Notably, proinflammatory M1 macrophages derived from THP-1 expressed high levels of FCN1 and IL-1ß, and FCN1 overexpression in THP-1-derived macrophages strongly promoted LPS-induced activation of the proinflammatory cytokine IL-1ß via the NLRP3-caspase-1 axis. CONCLUSIONS: FCN1 is a novel and promising diagnostic biomarker for PIBD. FCN1+ macrophages enriched in the colonic mucosa of PIBD exhibit proinflammatory phenotypes, and FCN1 promotes IL-1ß maturation in macrophages via the NLRP3-caspase-1 axis.

A large-scale plasma proteome Mendelian randomization study identifies novel causal plasma proteins related to primary biliary cholangitis.

Background and aims: Primary biliary cholangitis (PBC) is a progressive chronic autoimmune cholestatic liver disease characterized by the destruction of small intrahepatic bile ducts leading to biliary cirrhosis. Liver biopsy is required in the diagnosis of Antimitochondrial antibody-negative patients. Therefore, novel biomarkers are needed for the non-invasive diagnosis of PBC. To identify novel biomarkers for PBC, we conducted large-scale plasma proteome Mendelian randomization (MR). Methods: A total of 21,593 protein quantitative trait loci (pQTLs) for 2297 circulating proteins were used and classified into four different groups. MR analyses were conducted in the four groups separately. Furthermore, the results were discovered and replicated in two different cohorts of PBC. Colocalization analysis and enrichment analysis were also conducted. Results: Three plasma proteins (ficolin-1, CD40 and protein FAM177A1) were identified and replicated as being associated with PBC. All of them showed significant protective effects against PBC. An increase in ficolin-1 (OR=0.890 [0.843-0.941], p=3.50×10-5), CD40 (OR=0.814 [0.741-0.895], p=1.96×10-5) and protein FAM177A1 (OR=0.822 [0.754-0.897], p=9.75×10-6) reduced the incidence of PBC. Ficolin-1 (PP4 = 0.994) and protein FAM177A1 (PP4 = 0.995) colocalized with the expression of the genes FCN1 and FAM177A1 in whole blood, respectively. Furthermore, CD40 (PP4 = 0.977) and protein FAM177A1 (PP4 = 0.897) strongly colocalized with PBC. Conclusions: We expand the current biomarkers for PBC. In total, three (ficolin-1, CD40, and protein FAM177A1) plasma proteins were identified and replicated as being associated with PBC in MR analysis. All of them showed significant protective effects against PBC. These proteins can be potential biomarkers or drug targets for PBC.

Association of ficolin-1 and ficolin-3 gene variation and pulmonary tuberculosis susceptibility in a Chinese population.

BACKGROUND: The aim of our study was to estimate the association of ficolin-1 (FCN1) gene (rs10120023, rs1071583) and ficolin-3 (FCN3) gene (rs3813800, rs10794501) polymorphisms and pulmonary tuberculosis (PTB) susceptibility, as well as their several clinical features, in a Chinese population. METHODS: This study included a cohort of 489 PTB patients and 489 healthy controls, and the four SNPs were genotyped by improved multiple ligase detection reaction (iMLDR). RESULTS: We found that there were no significant differences regarding the allele and genotype frequencies of FCN1 rs10120023, rs1071583 and FCN3 rs3813800, rs10794501 between PTB patients and healthy controls (all p > 0.05). The association of three main haplotypes (CC, CT, and TC) in FCN1 and three main haplotypes (CT, GA, and GT) in FCN3 with PTB susceptibility was also analyzed, and no significant association was detected (all p > 0.05). In FCN1, the rs1071583 TT genotype was significantly associated with the occurrence of drug resistance in PTB patients (p = 0.040). In addition, the GG genotype and G allele frequencies of rs3813800 in FCN3 gene were significantly higher in PTB patients with pulmonary infection (p = 0.027, p = 0.020, respectively). CONCLUSIONS: FCN1 and FCN3 genetic variation were not contributed to the pathogenesis of PTB in Chinese. While rs1071583 and rs3813800 variant might associate with several clinical characteristics of PTB.

NCF2, MYO1F, S1PR4, and FCN1 as potential noninvasive diagnostic biomarkers in patients with obstructive coronary artery: A weighted gene co-expression network analysis.

This study aims to explore the predictive noninvasive biomarker for obstructive coronary artery disease (CAD). By using the data set GSE90074, weighted gene co-expression network analysis (WGCNA), and protein-protein interactive network, construction of differentially expressed genes in peripheral blood mononuclear cells was conducted to identify the most significant gene clusters associated with obstructive CAD. Univariate and multivariate stepwise logistic regression analyses and receiver operating characteristic analysis were used to predicate the diagnostic accuracy of biomarker candidates in the detection of obstructive CAD. Furthermore, functional prediction of candidate gene biomarkers was further confirmed in ST-segment elevation myocardial infarction (STEMI) patients or stable CAD patients by using the datasets of GSE62646 and GSE59867. We found that the blue module discriminated by WGCNA contained 13 hub-genes that could be independent risk factors for obstructive CAD (P < .05). Among these 13 hub-genes, a four-gene signature including neutrophil cytosol factor 2 (NCF2, P = .025), myosin-If (MYO1F, P = .001), sphingosine-1-phosphate receptor 4 (S1PR4, P = .015), and ficolin-1 (FCN1, P = .012) alone or combined with two risk factors (male sex and hyperlipidemia) may represent potential diagnostic biomarkers in obstructive CAD. Furthermore, the messenger RNA levels of NCF2, MYO1F, S1PR4, and FCN1 were higher in STEMI patients than that in stable CAD patients, although S1PR4 showed no statistical difference (P > .05). This four-gene signature could also act as a prognostic biomarker to discriminate STEMI patients from stable CAD patients. These findings suggest a four-gene signature (NCF2, MYO1F, S1PR4, and FCN1) alone or combined with two risk factors (male sex and hyperlipidemia) as a promising prognostic biomarker in the diagnosis of STEMI. Well-designed cohort studies should be implemented to warrant the diagnostic value of these genes in clinical purpose.

Associations of Ficolins With Hematological Malignancies in Patients Receiving High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantations.

A prospective study of 312 patients [194 with multiple myeloma (MM) and 118 with lymphomas (LYMPH)] receiving high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT) was conducted. Ficolins are innate immune defense factors, able to distinguish between "self" "abnormal self," and "non-self" and contribute to the elimination of the last two by direct opsonization and/or initiation of complement activation via the lectin pathway. Concentrations of ficolin-1, ficolin-2, and ficolin-3 in serially taken serum samples were determined as were the polymorphisms of the corresponding (FCN1, FCN2, and FCN3) genes. Serum samples were collected before conditioning chemotherapy, before HSCT, and once weekly post-HSCT (four to five samples in total); some patients were also sampled at 1 and/or 3 months post-transplantation. The control group (C) consisted of 267 healthy unrelated individuals. Median ficolin-1 and ficolin-2 (but not ficolin-3) levels in MM patients' sera taken before chemotherapy were lower (and correspondingly frequencies of the lowest concentrations were higher) compared with controls. That appeared to be associated with the malignant disease itself rather than with post-HSCT complications (febrile neutropenia, infections accompanied, or not with bacteremia). Higher frequencies of the FCN1 genotype G/A-C/C-G/G (corresponding to polymorphisms at positions -542, -144, and +6658, respectively) and FCN2 gene heterozygosity for the -857 C>A polymorphism were found among patients diagnosed with MM compared with the C group. Furthermore, FCN2 G/G homozygosity (-557 A>G) was found more frequently and heterozygosity G/T at +6424 less frequently among LYMPH patients than among the healthy subjects. Heterozygosity for +1637delC mutation of the FCN3 gene was more common among patients diagnosed with lymphomas who experienced hospital infections. Although no evidence for an association of low ficolin-1 or ficolin-2 with infections during neutropenia following chemotherapy before HSCT was found, we observed a possible protective effect of ficolins during follow-up.

Sickening or Healing the Heart? The Association of Ficolin-1 and Rheumatic Fever.

Rheumatic fever (RF) and its subsequent progression to rheumatic heart disease (RHD) are chronic inflammatory disorders prevalent in children and adolescents in underdeveloped countries, and a contributing factor for high morbidity and mortality rates worldwide. Their primary cause is oropharynx infection by Streptococcus pyogenes, whose acetylated residues are recognized by ficolin-1. This is the only membrane-bound, as well as soluble activator molecule of the complement lectin pathway (LP). Although LP genetic polymorphisms are associated with RF, FCN1 gene's role remains unknown. To understand this role, we haplotyped five FCN1 promoter polymorphisms by sequence-specific amplification in 193 patients (138 with RHD and 55, RF only) and 193 controls, measuring ficolin-1 serum concentrations in 78 patients and 86 controls, using enzyme-linked immunosorbent assay (ELISA). Patients presented lower ficolin-1 serum levels (p < 0.0001), but did not differ according to cardiac commitment. Control's genotype distribution was in the Hardy-Weinberg equilibrium. Four alleles (rs2989727: c.-1981A, rs10120023: c.-542A, rs10117466: c.-144A, and rs10858293: c.33T), all associated with increased FCN1 gene expression in whole blood or adipose subcutaneous tissue (p = 0.000001), were also associated with increased protection against the disease. They occur within the *3C2 haplotype, associated with an increased protection against RF (OR = 0.41, p < 0.0001) and with higher ficolin-1 levels in patient serum (p = 0.03). In addition, major alleles of these same polymorphisms comprehend the most primitive *1 haplotype, associated with increased susceptibility to RF (OR = 1.76, p < 0.0001). Nevertheless, instead of having a clear-cut protective role, the minor c.-1981A and c.-144A alleles were also associated with additive susceptibility to valvar stenosis and mitral insufficiency (OR = 3.75, p = 0.009 and OR = 3.37, p = 0.027, respectively). All associations were independent of age, sex or ethnicity. Thus, minor FCN1 promoter variants may play a protective role against RF, by encouraging bacteria elimination as well as increasing gene expression and protein levels. On the other hand, they may also predispose the patients to RHD symptoms, by probably contributing to chronic inflammation and tissue injury, thus emphasizing the dual importance of ficolin-1 in both conditions.

The pattern recognition molecule ficolin-1 exhibits differential binding to lymphocyte subsets, providing a novel link between innate and adaptive immunity.

Ficolin-1 is a soluble pattern recognition molecule synthesized by myeloid cells and capable of activating the lectin pathway of complement on the surface of pathogens. It is tethered to the membranes of monocytes and granulocytes; however, the biological significance of cell-associated ficolin-1 is unknown. Recognition of healthy host cells by a pattern recognition molecule constitutes a potential hazard to self cells and tissues, emphasizing the importance of further elucidating the reported self-recognition. In the current study we investigated the potential recognition of lymphocytes by ficolin-1 and demonstrated that CD56(dim) NK-cells and both CD4(+) and CD8(+) subsets of activated T-cells were recognized by ficolin-1. In contrast we did not detect binding of ficolin-1 to CD56(bright) NK-cells, NKT-cells, resting T-cells or B-cells. Furthermore, we showed that the protein-lymphocyte interaction occurred via the pathogen-recognition domain of ficolin-1 to sialic acid on the cell surface. Thus, the differential binding of ficolin-1 to lymphocyte subsets suggests ficolin-1 as a novel link between innate and adaptive immunity. Our results provide new insight about the recognition properties of ficolin-1 and point toward additional immune modulating functions of the molecule besides its role in pathogen recognition.