S100A4 Expression Research Articles

S100A8 regulates postoperative responses following tooth extraction in rats.

The reduction in alveolar ridge height and width after tooth extraction poses a substantial challenge for dental implant restoration. This study aimed to observe the roles of S100A8 in the inflammatory response and bone resorption following tooth extraction. Rat mandibular second molars were extracted. Western blotting, micro-computed tomography, tartrate-resistant acid phosphatase staining, immunohistochemistry, scanning electron microscopy (SEM), and immunofluorescence were applied to observe inflammatory responses and bone resorption after rat mandibular second molar extraction. S100A8 was overexpressed in RAW 246.7 cells, and transfection efficiency was confirmed using western blotting and immunofluorescence. Receptor Activator for Nuclear Factor-κB Ligand (RANKL)-induced osteoclastogenesis of RAW 246.7 cells and a lipopolysaccharide-stimulated environment were chosen to evaluate the roles and related mechanisms of S100A8. An increase in S100A8 expression was observed 2weeks after molar extraction compared to normal gingival tissues. Subsequently, S100 expression decreased between the second and third weeks, coinciding with the progression of inflammatory response following tooth extraction. Positive S100A8 expression was detected in the infiltrating cells and osteoclasts. S100A8 overexpression in RAW 246.7 cells promoted tumor necrosis factor-α expression and osteoclast formation by activating nuclear factor (NF)-κB p65 signaling. In summary, S100A8 was involved in inflammatory responses and bone resorption following tooth extraction by activating NF-κB p65 signaling. Interventions targeted to decrease S100A8 levels may have therapeutic implications for minimizing post-extraction bone loss.

The Slovenian translational platform GlioBank for brain tumour research: identification of molecular signatures of glioblastoma progression

Abstract Background Glioblastoma (GB) is one of the most lethal solid tumours in humans, with an average patient life expectancy of 15 months and 5-year survival rate of 5–10%. GB is still uncurable due to tumour heterogeneity and invasive nature as well as therapy-resistant cancer cells. Centralised biobanks with clinical data and corresponding biological material of GB patients facilitate the development of new treatment approaches and the search for clinically relevant biomarkers, with the goal of improving outcomes for GB patients. The aim of this study was firstly to establish a Sloveniantranslation platform, GlioBank, and secondly to demonstrate its utility through the identification of molecular signatures associated with GB progression and patient survival. Methods GlioBank contains tissue samples and corresponding tumour models as well as clinical data from patients diagnosed with glioma, with a focus on GB. Primary GB cells, glioblastoma stem cells (GSCs) and organoids have been established from fresh tumour biopsies. We performed expression analyses of genes associated with GB progression and bioinformatics analyses of available clinical and research data obtained from a subset of 91 GB patients. qPCR was performed to determine the expression of genes associated with therapy- resistance and cancer cell invasion, including markers of different GB subtypes, GSCs, epithelial-to-mesenchymal transition, and immunomodulation/chemokine signalling in tumour tissues and corresponding cellular models. Results GlioBank contains biological material and research, and clinical data collected in the SciNote electronic laboratory notebook. To date, more than 240 glioma tissue samples have been collected and stored in GlioBank, most of which are GB tissues (205) and were further processed to establish primary GB cells (n=64), GSCs (n=14), and GB organoids (n=17). Corresponding blood plasma (n=103) and peripheral blood mononuclear cells (n=101) are also stored. GB tumours were classified into four different subtypes that differed regarding patient survival; the mixed subtype exhibited the longest patient survival. High DAB2, S100A4, and STAT3 expression was associated with poor overall patient survival, and DAB2 was found to be an independent prognostic marker for GB survival. We analysed the molecular signatures between different tumour regions (core vs. rim). STMN4, ERBB3, and ACSBG1 were upregulated in the tumour rim, suggesting that these genes are associated with the invasive nature of GB. Conclusions GlioBank is a centralised biobank that has been built by a multidisciplinary network with the aim to facilitate disease-oriented basic and clinical research. The advantages of GlioBank include the molecular characterization of GB based on targeted gene expression, the availability of diverse cellular models (e.g. GB cells and organoids), and a large number of patient-matched tumour core and rim samples, all with accompanying molecular and clinical data. We report here for the first time an association between DAB2 expression and low overall survival in GB patients, indicative of a prognostic value of DAB2.

S100A8-CAMKK2-AMPK axis confers the protective effects of mild hypothermia against cerebral ischemia-reperfusion injury in rats

To investigate the neuroprotective mechanism of mild hypothermia (MH) in ameliorating cerebral ischemia reperfusion (IR) injury. The Pulsinelli’s four-vessel ligation method was utilized to establish a rat model of global cerebral IR injury. To investigate the role of S100A8 in MH treatment of cerebral IR injury, hippocampus-specific S100A8 loss or gain of function was achieved using an adeno-associated virus system. We examined the effect of S100A8 over-expression or knock-down on the function of the SH-SY5Y cell line subjected to oxygen-glucose deprivation reoxygenation (OGDR) injury under MH treatment and delved into the underlying mechanisms. MH significantly ameliorates IR-induced neurological injury in the brain. Similarly to MH, knock-down of S100A8 significantly reduced neuronal oxidative stress, attenuated mitochondrial damage, inhibited apoptosis, and improved cognitive function in IR rats. Conversely, over-expression of S100A8 attenuated MH’s protective effect and aggravated brain IR injury. In vitro, low expression of S100A8 significantly inhibited the decline in mitochondrial membrane potential induced by OGDR, reduced oxidative stress response, and decreased cell apoptosis, acting as a protective agent nearly equivalent to MH in SH-SY5Y cells. However, over-expression of S100A8 significantly inhibited these protective effects of MH. Mechanistically, MH down-regulated S100A8 expression, enhancing mitochondrial function via activation of the CAMKK2/AMPK signaling pathway. Moreover, with MH treatment, the administration of CAMKK2 and AMPK inhibitors STO-609 and Dorsomorphin significantly increased oxidative stress, mitochondrial damage, and cell apoptosis, thereby diminishing MH’s neuroprotective effect against cerebral IR injury. Our study identified S100A8 as a master regulator that enables MH to ameliorate neurological injury during the early stage of cerebral IR injury by enhancing mitochondrial function. By targeting the S100A8-initiated CAMKK2/AMPK signaling pathway, we may unlock a novel therapeutic intervention or develop a refined MH therapeutic strategy against cerebral IR injury.

Oncogene OSTM1 Promotes Gastric-Cancer Metastasis by Modulating the Metastatic Microenvironment Through Altered Tumor-Cell Autocrine Signaling.

Gastric cancer remains a malignancy with high incidence, mortality rates, and poor prognosis globally. Osteoclastogenesis-associated transmembrane protein 1 (OSTM1), a transmembrane protein overexpressed in various tumors, has unclear functions in gastric-cancer progression. This study explores OSTM1's role in gastric-cancer proliferation and metastasis. OSTM1 expression was analyzed in gastric-cancer and adjacent tissues using immunohistochemistry and RT-qPCR. OSTM1 overexpression and knockdown cell lines were established to assess its effects on cancer-cell behavior through in vitro and in vivo experiments. Western blot and RT-qPCR were used to examine OSTM1's regulation of S100A4 expression. OSTM1 was significantly overexpressed in gastric-cancer tissues, negatively correlating with TNM staging and overall survival. OSTM1 overexpression enhanced cancer-cell proliferation, colony formation, migration, and invasion, while its knockdown showed opposite effects. In vivo studies confirmed increased lung metastatic capability in high OSTM1-expressing cells. Mechanistically, OSTM1 positively regulated S100A4 expression, with S100A4 knockdown reducing OSTM1-enhanced metastasis. Gastric-cancer lung metastases showed higher microvascular density and α-SMA-positive fibroblast infiltration in the OSTM1 high-expression group. OSTM1 promotes gastric-cancer progression by upregulating S100A4 and modifying the tumor microenvironment through enhanced angiogenesis and fibroblast activation. OSTM1 represents a potential diagnostic and prognostic biomarker, with the OSTM1-S100A4 axis offering new therapeutic possibilities for gastric-cancer treatment.

Prognostic Significance of S100A4 in Ovarian Clear Cell Carcinoma: Its Relation to Tumor Progression and Chemoresistance.

S100A4, a small calcium-binding protein, promotes metastasis in a variety of human malignancies, but little is known about its involvement in ovarian clear cell carcinoma (OCCC). Herein, we characterized the functional role of S100A4 in this tumor type. We analyzed immunohistochemical sections from 120 OCCC patients. OCCC cell lines in which S100A4 was knocked out (KO) or overexpressed were also used to study the protein's effects. Stable overexpression of S100A4 decreased the proliferation of OCCC cell lines (concomitant with more cells in G1 and fewer in the G2/M phase of the cell cycle). S100A4 overexpression also reduced susceptibility to cisplatin-induced apoptosis (probably due to an increased BCL2: BAX ratio), accelerated epithelial-mesenchymal transition (EMT)-related cell mobility, and enhanced cancer stem cell (CSC) properties (including increases in both spheroid formation and in the aldehyde dehydrogenase 1 (ALDH1)high population). In contrast, S100A4 KO generally induced the opposite phenotypes, although it did not affect migration capability. In clinical OCCC samples, high S100A4 expression was associated with a low frequency of cleaved poly-(ADP-ribose) polymerase 1-positive apoptotic cells, a reduced proliferative rate, and expression of high ALDH1 and vimentin levels. In addition, a high S100A4 score was a significant (but not independent) prognostic factor in OCCC. Our findings suggest that S100A4 may be an unfavorable prognostic factor in OCCC, as it accelerates tumor progression and promotes chemoresistance through the modulation of proliferation, susceptibility to apoptosis, and EMT/CSC properties.

Study on the expression of S100A4 and HMGA1 in endometrial carcinoma and their correlation with metastasis

Study on the expression of S100A4 and HMGA1 in endometrial carcinoma and their correlation with metastasis

Characteristics and multi-omics analysis of spontaneous spondyloarthritis in non-human primates: Case report.

Spondyloarthritis is a prevalent and persistent condition that significantly impacts the quality of life. Its intricate pathological mechanisms have led to a scarcity of animal models capable of replicating the disease progression in humans, making it a prominent area of research interest in the field. To delve into the pathological and physiological traits of spontaneous non-human primate spondyloarthritis, this study meticulously examined the disease features of this natural disease model through an array of techniques including X-ray imaging, MRI imaging, blood biochemistry, markers of bone metabolism, transcriptomics, proteomics, and metabolomics. X-ray imaging results revealed that crab-eating monkeys (Macaca fascicularis) with spontaneous spondyloarthritis developed bone spurs in the spine and experienced bone destruction in peripheral joints. MRI imaging further confirmed inflammatory changes in the spine and facet joints of these monkeys, along with inflammation and bone destruction in peripheral joints. Blood biochemistry analysis showed abnormalities in liver function and kidney function indicators in crab-eating monkeys with spontaneous spondyloarthritis. Analysis of bone metabolism-related markers showed a decrease in bone formation (BGP) and bone resorption (β-CTx). A thorough correlation analysis was conducted on the transcriptome and proteome expression data, revealing a significant positive correlation between the two datasets. A total of eight genes and proteins with high expression levels were identified as common to both the transcriptome and proteome. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on these co-expressed genes and proteins, indicating a predominant enrichment in the IL-17 signaling pathway, with S100A8 and S100A9 identified as the core proteins. Further analysis using clinical data in conjunction with proteome data through Weighted Gene Co-expression Network Analysis (WGCNA) demonstrated a significant positive correlation between the high expression of S100A8 and S100A9 and the clinical phenotypes of spinal abnormalities, thereby corroborating the close association of S100A8 and S100A9 with the phenotype of spondyloarthritis. Human clinical studies have already established a link between S100A8 and S100A9 and autoimmune-related arthritic diseases, suggesting that the spontaneous spondyloarthritis observed in crab-eating macaques may be related to autoimmune diseases. It is hypothesized that S100A8 and S100A9 could serve as potential predictive biomarkers for spondyloarthritis in non-human primates.

Preliminary screening of new biomarkers for sepsis using bioinformatics and experimental validation.

The morbidity and mortality of sepsis remain high, and so far specific diagnostic and therapeutic means are lacking. To screen novel biomarkers for sepsis. Raw sepsis data were downloaded from the Chinese National Genebank (CNGBdb) and screened for differentially expressed RNAs. Key genes with predictive value were identified through weighted correlation network analysis (WGCNA) and meta-analysis and survival analysis using multiple public databases. Core genes were analyzed for functional enrichment using Gene Set Enrichment Analysis(GSEA). The core genes were localized using single-cell sequencing. qPCR was used to validate the core genes. Differential analysis yielded a total of 5125 mRNA. WGCNA identified 5 modules and screened 3 core genes (S100A11, QPCT, and IFITM2). The prognosis of sepsis patients was strongly linked to S100A11, QPCT, and IFITM2 based on meta-analysis and survival analysis(P < 0.05).GSEA analysis showed that S100A11, QPCT, and IFITM2 were significantly enriched in ribosome-related pathways. S100A11 and QPCT were widely distributed in all immune cells, and QPCT was mainly localized in the macrophage cell lineage. In the sepsis group, the qPCR results showed that S100A11, QPCT, and IFITM2 expression levels were significantly higher in the sepsis group(P < 0.05). In this study, S100A11, QPCT, and IFITM2 were screened as new potential biomarkers for sepsis. Validated by bioinformatics analysis and qPCR, these genes are closely associated with the prognosis of sepsis patients and have potential as diagnostic and therapeutic targets.

VDAC1-NF-κB/p65-mediated S100A16 contributes to myocardial ischemia/reperfusion injury by regulating oxidative stress and inflammatory response via Calmodulin/CaMKK2/AMPK pathway

Myocardial injury triggers intense inflammatory reactions and oxidative stress responses. S100 calcium-binding protein A16 (S100A16), a multi-functional calcium (Ca2+)-binding protein, participates in inflammatory responses and contributes to ischemia/reperfusion (I/R) injury. Nevertheless, the precise mechanism by which S100A16 operates in myocardial I/R injury remains uncertain. Cardiac I/R injury was produced by ligation/release of the left anterior descending artery, and mouse cardiac cells were subjected to hypoxia/reoxygenation (H/R) to determine the biological effects in vitro. We demonstrated that S100A16 was upregulated in the ischemic hearts and cardiac cells after I/R and H/R injury. Adenovirus-mediated S100A16 inhibition led to a considerable improvement in cardiac function with a reduced infarct size, accompanied by a reduction in cardiomyocyte apoptosis. Similar effects of S100A16 inhibition on inflammation and reactive oxygen species (ROS) production were observed in cultured cardiomyocytes. Importantly, we showed that I/R and H/R treatment upregulated the expression of voltage-dependent anion channel 1 (VDAC1), which subsequently activated NF-κB/p65 to facilitate the binding of NF-κB/p65 to the S100A16 promoter, thereby activating the transcription and expression of S100A16. Mechanically, S100A16 responded to increasing Ca2+ and interacted with calmodulin (CaM) to regulate the activation of calcium/calmodulin-dependent protein kinase 2 (CAMKK2)/AMPK pathway. In conclusion, VDAC1 sustained the NF-κB p65 pathway activation to elicit increased S100A16 expression, contributing to myocardial damage and heart failure post-I/R via the CaM/CaMKK2/AMPK pathway. This study revealed a crucial role of the VDAC1-S100A16 axis in the process of myocardial I/R injury, providing novel molecular targets for the treatment of cardiac conditions associated with I/R injury.

S100A4 Exerts Neuroprotective Effects by Attenuating Blood-Brain Barrier Disruption and Oxidative Stress via the PI3K/Akt/Nrf2 Axis in Ischemic Stroke

Ischemic stroke is a major cause of disability and mortality worldwide, with oxidative stress and blood-brain barrier (BBB) injury playing crucial roles in its pathogenesis. Our RNA sequencing results revealed that S100 calcium-binding protein A4 (S100A4) is highly expressed in the middle cerebral artery occlusion (MCAO) mouse model. We analyzed S100A4 expression in ischemic stroke patients and in mice subjected to the MCAO model. Moreover, using adeno-associated virus (AAV)-mediated knockdown of S100A4 in mice, we evaluated its effects on neurological deficits, BBB integrity, and oxidative stress in MCAO mice. Bioinformatic analyses explored the potential downstream pathways of S100A4.S100A4 expression was significantly elevated in the serum of ischemic stroke patients and brain tissues of MCAO mice. AAV-mediated knockdown of S100A4 exacerbated neurological deficits, BBB disruption, and oxidative stress in MCAO mice. The upregulation of S100A4 mitigated these outcomes, which were facilitated through the stimulation of the PI3K/Akt/Nrf2 signaling cascade.Our results illustrate that S100A4 plays a protective role in preventing neuronal damage during ischemic stroke by reducing oxidative stress and preserving BBB integrity through the PI3K/Akt/Nrf2 pathway. This highlights its promise as a potential therapeutic approach for ischemic stroke.

Renal tubular S100A7a impairs fatty acid oxidation and exacerbates renal fibrosis via both intracellular and extracellular pathway.

A couple of S100 family proteins (S100s) have been reported to exert pro-inflammatory functions in the progression of renal fibrosis (RF). Unlike some S100s which are expressed by both epithelial and stromal inflammatory cells, S100A7 is restricted expressed in epithelium. Persistent S100A7 expression occurs in some invasive carcinomas and is associated with poor prognostic factors. Whereas, whether it is implicated in renal tubular epithelial cell injury and kidney disease remains unexplored. In this study, we demonstrate that S100A7 is highly upregulated in tubular cells of both mouse renal fibrotic lesions and human kidney biopsies from patients with chronic kidney disease (CKD). The level of renal S100A7 was associated with both the decline of renal function and the progression of renal fibrosis in CKD patients. Overexpressing S100A7a impaired fatty acid oxidation (FAO) and promoted lipid peroxidation in proximal tubular cells (PTCs). Mechanistically, S100A7a interacts with β-catenin, thereby preventing its ubiquitination and degradation by the β-TrCP-SCF complex, and in turn activated β-catenin signaling, downregulated the expression of PGC-1α. Additionally, S100A7a exacerbated lipid peroxidation via RAGE-p-ERK-NOX2 pathway. Specific deletion of S100a7a in tubular cells enhanced fatty acid oxidation (FAO) and reduced lipid peroxidation, resulting in improved renal function and alleviation of renal fibrosis induced by unilateral ureteral obstruction and unilateral ischemia-reperfusion injury. Collectively, we delineate a previously unrecognized function of S100A7a in the progression of RF.

S100A4 contributes to colorectal carcinoma aggressive behavior and to chemoradiotherapy resistance in locally advanced rectal carcinoma

To investigate the functional role of S100A4 in advanced colorectal carcinoma (Ad-CRC) and locally advanced rectal carcinoma (LAd-RC) receiving neoadjuvant chemoradiotherapy (NCRT). We analyzed histopathological and immunohistochemical sections from 150 patients with Ad-CRC and 177 LAd-RC patients treated with NCRT. S100A4 knockout (KO) HCT116 cells were also used. S100A4 expression was absent in normal mucosa but increased progressively from colorectal adenoma to carcinoma, suggesting that S100A4 regulation is an early event in colorectal carcinogenesis. In Ad-CRC, high S100A4 expression correlated with high tumor budding and nuclear β-catenin, deep invasion, lymph-vascular involvement, and unfavorable prognosis. In NCRT-treated LAd-RC, high S100A4 expression was associated with poor treatment response and short progression-free survival. S100A4 KO decreased the proliferation of HCT116 cells through activation of the p53/p21waf1 axis, and sensitized cells to adriamycin-induced apoptosis. Levels of the apoptotic marker, cleaved poly (ADP-ribose) polymerase 1, were significantly higher in samples with low S100A4 and wild type p53. Finally, we observed a direct interaction between S100A4 and p53. In conclusion, S100A4 expression engenders aggressive behavior in Ad-CRC through association with β-catenin-driven tumor buddings. S100A4 exerts anti-apoptotic and proliferative effects via inhibition of p53 in LAd-RC patients receiving NCRT, which leads to chemoradioresistance and poor prognosis.

CXCL4 deficiency limits M4 macrophage infiltration and attenuates hyperoxia-induced lung injury

BackgroundBronchopulmonary dysplasia (BPD), a chronic lung disease prevalent among premature infants, significantly impacts lifelong respiratory health. Macrophages, as key components of the innate immune system, play a role in lung tissue inflammation and injury, exhibiting diverse and dynamic functionalities. The M4 macrophage, a distinctive subtype primarily triggered by chemokine (C-X-C motif) ligand 4 (CXCL4), has been implicated in pulmonary inflammatory and fibrotic processes. Nonetheless, its contribution to the pathophysiology of BPD remains uncertain.ObjectiveThis study aimed to elucidate the involvement of CXCL4 in hyperoxia-induced neonatal lung injury and fibrosis, with a particular focus on its influence on M4 macrophages.MethodsA BPD model in neonatal mice was established through continuous exposure to 95% O2 for 7 days. Comparative analyses of lung damage and subsequent regeneration were conducted between wild-type (WT) and CXCL4 knockout (KO) mice. Lung tissue inflammation and fibrosis were assessed using histological and immunofluorescence staining, enzyme-linked immunosorbent assay, Western blot, and real-time quantitative polymerase chain reaction. Differentiation of M0 and M4 macrophages was performed in vitro using macrophage colony-stimulating factor and CXCL4, while expressions of S100A8 and MMP7, along with migration assays, were evaluated.ResultsElevated CXCL4 levels and M4 macrophage activation were identified in the lung tissue of BPD model mice. CXCL4 deficiency conferred protection to alveolar type 2 epithelial cells, reduced sphingosine-1-phosphate metabolic activity, mitigated pulmonary fibrosis, and limited M4 macrophage progression. This deletion further enhanced lung matrix remodeling during recovery. In vitro, CXCL4 promoted M4 macrophage differentiation and increased macrophage migration via chemokine (C-C motif) receptor 1.ConclusionCXCL4 contributes to hyperoxia-induced lung injury and fibrosis through modulation of cytokine release, alveolar cell proliferation, lipid metabolism, and the regulation of macrophage phenotype and function.

S100A11 is a potential prognostic biomarker and correlated with tumor immunosuppressive microenvironment in glioma.

This study investigates the role of S100A11 as a potential biomarker for glioma-associated macrophages (GAMs) and its correlation with GAMs infiltration in glioblastoma multiforme, aiming to better understand the immune microenvironment of glioma. We conducted a comprehensive study using various techniques and approaches. First, we examined the expression of S100A11 on GAMs through Western blot, immunohistochemistry, and immunofluorescence analyses. Additionally, we utilized single-cell sequencing data and immune infiltration analysis to establish the relationship between S100A11 and GAMs infiltration in glioma. Our findings revealed that S100A11 was highly expressed on GAMs, as validated by Western blot, immunohistochemistry, and immunofluorescence. Moreover, S100A11 exhibited a strong correlation with GAMs infiltration, as evidenced by single-cell data and immune infiltration analysis. These results highlight the significant association of S100A11 with the immune microenvironment surrounding glioma. S100A11 emerges as a promising candidate for regulating glioma immunosuppression and may serve as a potential marker for GAMs. This study sheds light on the crucial role of S100A11 in the crosstalk between GAMs and glioma cells, contributing to our understanding of glioma progression within the tumor microenvironment.

S100A9 Inhibition Mitigates Acute Pancreatitis by Suppressing RAGE Expression and Subsequently Ameliorating Inflammation.

Acute pancreatitis (AP) is a common acute inflammatory abdominal condition. Severe acute pancreatitis (SAP) can provoke a systemic inflammatory response and lead to multiple organ failure. The S100A9 protein, recognized as a major inflammatory biomarker, plays a significant role in both infection and inflammatory responses. Despite its known role in inflammation, the precise role of S100A9 in AP remains poorly understood. This study aimed to elucidate the potential role of S100A9 in AP and investigate the underlying mechanism. We employed a mouse model of AP and the AR42J cell line to investigate the functional role of S100A9. The effect of S100A9 on pancreatic injury and the expression of inflammatory factors (IL-6, IL-1β, and TNF-α) was assessed through targeted inhibition of S100A9 expression in the mouse model of AP. Furthermore, the modulatory effect of cerulein-induced inflammatory responses on AR42J cells was assessed after adding the S100A9 recombinant protein. In the mouse model of AP, targeted inhibition of S100A9 markedly ameliorated pancreatic injury and significantly decreased the expression levels of IL-6, IL-1β, and TNF-α. Moreover, increased levels of S100A9 were positively correlated with elevated expression of receptor for advanced glycation endproducts (RAGE) in pancreatic acinar cells. In AR42J cells, the introduction of S100A9 recombinant protein enhanced RAGE expression and exacerbated cerulein-induced inflammatory response. S100A9 inhibition significantly alleviated the pancreatic inflammatory response by downregulating RAGE expression, thereby improving AP.

Potential Serum HMGB1, HSP90, and S100A9 as Metastasis Predictive Biomarkers for Cancer Patients and Relevant Cytokines: A Pilot Study.

Metastatic cancer is still one of the leading causes of death worldwide despite significant advancements in diagnosis and treatment. Biomarkers are one of the most promising diagnostic tools that are used alongside traditional diagnostic tools in cancer patients. DAMPs are intracellular molecules released in response to cellular stress, tissue injury, and cell death. There have been shown to be associated with worsening prognosis among such patients, and some DAMPs could potentially be used as predictive biomarkers of metastatic status. The goal of this study is to investigate DAMP expression and the probability that certain DAMPs could be predictive biomarkers of the metastatic stage in various cancer types. Forty cancer patients at Naresuan University Hospital, Thailand, were enrolled. Then, an investigation of HSP90, HMGB1, S100A9, and ATP expression and cytokine/chemokine profiling in serum was performed using an immunological-based assay. We assessed the predictive biomarker candidates and the association between DAMP expression and cytokines/chemokines using an ROC curve analysis and a correlation regression analysis. The results showed that HSP90 has strong potential as a metastatic predictive biomarker, with a cutoff value of 25.46 ng/mL (AUC 0.8207, sensitivity 82.61%, specificity 75.00%, 95% CI 0.6860-0.9553). This was followed by HMGB1 and S100A9, which exhibited sensitivity of 82.61 and 65.22%, and specificity of 68.75 and 56.25%, respectively. Interestingly, the candidate DAMPs negatively correlate with various serum cytokines, for example, HMGB1 vs. IL-15 (slope 88.05, R 0.3297, p-value 0.005), HMGB1 vs. IFN-γ (slope 2.235, R 0.3052, p-value 0.0013) and HSP90 vs. IFN-γ (slope 0.0614, R 0.2187, p-value 0.008), suggesting that they are highly elevated in advanced metastatic tumors, which is possibly associated with the immunomodulation effect. We postulated that HSP90, HMGB1, and S100A9 have the potential to be predictive biomarkers for supporting tumor metastasis categorization using histopathology.

Orosomucoid 1 interacts with S100A12 and activates ERK signalling to expedite the advancement of bladder cancer

ABSTRACT The research endeavors to expound the role of ORM1 in bladder cancer (BCa) and the implied response mechanism. RT-qPCR and Western blotting examined ORM1 and S100A12 expression. Functional experiments assessed the cellular phenotypes. HDOCK and Co-IP confirmed the interaction of ORM1 and S100A12. Western blotting tested apoptosis- and ERK signaling-associated proteins. ORM1 and S100A12 were abundant in the BCa cells. ORM1 or S100A12 loss impaired cell proliferation, migration, and invasion, and aggravated cell apoptosis. ORM1 interacted with S100A12. ORM1 knockdown down-regulated S100A12 expression and inactivated ERK signaling.S100A12 overexpression or ERK activator reversed the impacts of ORM1 interference on ERK signaling and BCa cells. ORM1 mightdrive BCa via binding to S100A12 and activating ERK signaling.

A new perspective on macrophage-targeted drug research: the potential of KDELR2 in bladder cancer immunotherapy.

Bladder cancer was recognized as one of the most common malignant tumors in the urinary system, and treatment options remained largely limited to conventional surgery, radiotherapy, and chemotherapy, which limited patient benefits. Researchers constructed an RNA transcriptome map of bladder cancer by integrating single-cell RNA sequencing and clinical data, identifying potential molecular targets for diagnosis and treatment. We also verified the antitumor activity of the target through in vitro experiment. A distinct tumor cell subpopulation characterized by elevated S100A8 expression exhibited high copy number variation, high stemness, and low differentiation. It interacted with myeloid cells via the MIF-(CD74+CD44) and MIF-(CD74+CXCR4) signaling pathways. This study underscored KDELR2's role in promoting cell proliferation, invasion, and migration, providing new therapeutic insights. Prognostic analysis revealed that KDELR2 correlated with poor survival, higher immune scores, and increased macrophage infiltration. The findings suggested that patients with high KDELR2 expression might benefit from immune checkpoint therapy. KDELR2 was also shown to enhance bladder cancer cell proliferation, invasion, and migration, highlighting it as a promising target for macrophage-focused drug development.

S100A2 upregulates GLUT1 expression to promote glycolysis in the progression of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor. Among the S100 protein family members, the imbalance of S100 calcium-binding protein A2 (S100A2) was related to the pathogenesis of several types of cancer, and S100A2 has been reported to be upregulated in the plasma of NPC patients; however, its specific role in NPC pathogenesis remains unclear. Thus, this study aims to determine the potential role of S100A2 in NPC to provide novel insights into NPC management. C666-1 and NPC/HK-1 cells were transfected with S100A2 silencing/overexpression (si/oe) constructs. For in vivo investigations, NPC/HK-1 cells were transfected with si/oe-S100A2 to induce tumor formation in nude mice. Cellular viability and apoptosis were assessed using the CCK8 assay, colony-forming assay, and flow cytometry. Glucose uptake and lactate production levels were quantified using biochemical assays. S100A2 expression was measured via RT-qPCR, Western blot, immunohistochemistry, and immunofluorescence were performed to determine the levels of S100A2, PI3K, AKT, p-PI3K, p-AKT, GLUT1, HK-2, LDHA, and ki-67 proteins. S100A2 expression levels were significantly higher in NPC cancer tissues than in adjacent tissues. Similarly, C666-1 and NPC/HK-1 cells exhibited increased S100A2 expression, and silencing S100A2 significantly inhibited NPC cell viability, proliferation, glucose uptake, and lactate production, and induced apoptosis and decreased the protein levels of GLUT1, LDHA, and HK2 in NPC cells. Conversely, S100A2 overexpression enhanced these characteristics in NPC cells but could be mitigated by the PI3K/AKT inhibitor (LY294002). Silencing S100A2 suppressed the tumor formation of NPC/HK-1 cells, while S100A2 overexpression promoted tumor formation and could be hindered by a GLUT1 inhibitor (WZB117). S100A2 is upregulated in cancer tissues of NPC patients and was found to promote proliferation, glycolysis, and tumor formation in NPC cells through its interaction with GLUT1.

Monocytes generated by interleukin-6-treated human hematopoietic stem and progenitor cells secrete calprotectin that inhibits erythropoiesis.

Elevated circulating levels of calprotectin (CAL), the S100A8/A9 heterodimer, are biomarkers of severe systemic inflammation. Here, we investigate the effects of CAL on early human hematopoiesis. CAL demonstrates limited impact on gene expression in stem and progenitor cells, in contrast with interleukin-6 (IL6), which promotes the expression of the S100A8 and S100A9 genes in hematopoietic progenitors and the generation of monocytes that release CAL. The main target of CAL is an erythroid-megakaryocyte progenitor (EMP) subset. CAL prevents both erythropoietin-driven differentiation of healthy progenitors and JAK2-V617F-driven erythropoiesis. In the context of JAK2-V617F, CAL also promotes the expression of S100A8 and S100A9 genes in monocytes. The signature of CAL effects is detected in the bone marrow progenitors of patients with myeloid malignancy or severe infection. These results position CAL as a mediator of IL6 effects on triggering anemia during inflammation, an effect that is amplified in the context of JAK2-V617F-driven hematopoiesis.