Member Of S100 Protein Family Research Articles

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.

Clinical Significance of HRNR Expression in Patients With Stage II/III Gastric Cancer After Curative Gastrectomy.

The function of the S-100 protein family member hornerin (HRNR) in gastric cancer (GC) tissues is largely unknown. We researched the clinical significance of HRNR expression in GC tissues of patients with pathological (p)Stage II/III GC after curative resection. We included patients with pStage II/III GC who underwent curative gastrectomy (n=253). Expression levels of HRNR in GC tissue and in the adjacent normal mucosa were determined using quantitative real-time polymerase chain reaction. Clinicopathological features and overall survival (OS) were compared in patients with different HRNR expression levels in GC tissue. HRNR expression levels were significantly higher in GC tissues than in the adjacent normal mucosa. HRNR expression level in GC tissue showed sex differences. The 5-year OS rate in the high-HRNR expression group was significantly worse than that in the low-expression group (5-year survival 53.6% vs. 74.9%; p=0.004). Furthermore, on multivariate analysis, high-HRNR expression was an independent predictor of poor OS (hazard ratio=1.534; 95% confidence interval=1.130-2.618; p=0.011). In patients with pStage II/III GC after curative gastrectomy, HRNR expression in GC tissue may be a useful prognostic marker.

Recognition of granulocyte-macrophage colony-stimulating factor by specific S100 proteins

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic myelopoietic growth factor and proinflammatory cytokine, clinically used for multiple indications and serving as a promising target for treatment of many disorders, including cancer, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, COVID-19. We have previously shown that dimeric Ca2+-bound forms of S100A6 and S100P proteins, members of the multifunctional S100 protein family, are specific to GM-CSF. To probe selectivity of these interactions, the affinity of recombinant human GM-CSF to dimeric Ca2+-loaded forms of 18 recombinant human S100 proteins was studied by surface plasmon resonance spectroscopy. Of them, only S100A4 protein specifically binds to GM-CSF with equilibrium dissociation constant, Kd, values of 0.3–2 μM, as confirmed by intrinsic fluorescence and chemical crosslinking data. Calcium removal prevents S100A4 binding to GM-CSF, whereas monomerization of S100A4/A6/P proteins disrupts S100A4/A6 interaction with GM-CSF and induces a slight decrease in S100P affinity for GM-CSF. Structural modelling indicates the presence in the GM-CSF molecule of a conserved S100A4/A6/P-binding site, consisting of the residues from its termini, helices I and III, some of which are involved in the interaction with GM-CSF receptors. The predicted involvement of the ‘hinge’ region and F89 residue of S100P in GM-CSF recognition was confirmed by mutagenesis. Examination of S100A4/A6/P ability to affect GM-CSF signaling showed that S100A4/A6 inhibit GM-CSF-induced suppression of viability of monocytic THP-1 cells. The ability of the S100 proteins to modulate GM-CSF activity is relevant to progression of various neoplasms and other diseases, according to bioinformatics analysis. The direct regulation of GM-CSF signaling by extracellular forms of the S100 proteins should be taken into account in the clinical use of GM-CSF and development of the therapeutic interventions targeting GM-CSF or its receptors.

S100 Calcium Binding Protein A16 Promotes Cell Proliferation by triggering LATS1 ubiquitin degradation mediated by CUL4A ligase to inhibit Hippo pathway in Glioma development.

Background: S100 Calcium Binding Protein A16 (S100A16), a novel member of S100 protein family, is linked to tumorigenic processes and abundantly expressed in CNS tissues. Our study aimed to explore the biological function and possible mechanism of S100A16 in the progression of glioma. Methods: Sequence data of S100A16 and survival prognosis of glioma patients were initially analyzed using public databases. Glioma tissues were collected to examine S100A16 expression levels. Glioma cell lines and nude mice were subjected to in vitro and in vivo functional experiments. Western blot, immunofluorescence (IF), immunoprecipitation (IP) and ubiquitination assays were done to further elucidate the underlying mechanism. Results: This study firstly revealed that S100A16 was markedly up-regulated in glioma, and patients with higher S100A16 levels have a shorter survival time. S100A16 overexpression promoted the proliferation, invasion and migration of glioma cells, and the tumor formation of nude mice. Importantly, we identified S100A16 as a negative regulator of the Hippo pathway which could decrease LATS1 expression levels, promote the YAP nuclear import and initiate the downstream target genes CYR61 and CTGF. Moreover, our data showed that S100A16 destabilized LATS1 protein by inducing the CUL4A-mediated LATS1 ubiquitination degradation. Conclusions: This study demonstrated a vital biological role of S100A16 in glioma progression mechanism by promoting CUL4A-mediated LATS1 ubiquitination to inhibit Hippo signaling pathway. S100A16 could be a novel biomarker and treatment option for glioma patients.

Strongyloides venezuelensis-derived venestatin ameliorates asthma pathogenesis by suppressing receptor for advanced glycation end-products-mediated signaling

IntroductionEF-hand Ca2+-binding proteins such as S100 protein family members are recognized by the receptor for advanced glycation end-products (RAGE) and are involved in the pathogenesis of asthma/allergic airway inflammation (AAI). Venestatin, an EF-hand Ca2+-binding protein, which is secreted by the parasitic helminth Strongyloides venezuelensis, binds with RAGE and suppresses RAGE-mediated inflammatory responses after parasite invasion. In this study, we evaluated the effect of venestatin on pathogenesis in a house dust mite (HDM) murine model of asthma/AAI. MethodsMice were intranasally treated with HDM, HDM with recombinant venestatin, or HDM with synthetic peptides, which were designed based on the EF-hand Ca2+-binding domain of venestatin. Pro-inflammatory responses in the lungs of mice were assessed. ResultsHDM treatment induced inflammatory cell infiltration, phosphorylation of the mitogen-activated protein kinase and inhibitor κB, and production of the cytokines tumor necrosis factor-α and interleukin-5 in the lungs. Co-administration of recombinant venestatin with HDM suppressed these pro-inflammatory responses. Treatment with synthetic peptides reduced inflammatory cell infiltration in a RAGE-dependent manner. ConclusionThe EF-hand domain of venestatin may have potential therapeutic benefits in asthma.

Systematic screening identifies a TEAD4-S100A13 axis modulating cisplatin sensitivity of oral squamous cell carcinoma cells.

This study aimed to screen prognosis-related S100 protein family members in human paxpillomaviruses (HPV)-negative oral squamous cell carcinoma (OSCC) and their molecular regulations. Bioinformatic screening was conducted based on single-cell RNA-seq data from Puram 2017 dataset and bulk-seq data from the Cancer Genome Atlas (TCGA). HPV-negative OSCC cell lines CAL-27 and SCC-4 were used as in vitro cell models. Among 21 S100 protein family member genes, S100A13 upregulation was associated with unfavorable progression-free survival and disease-specific survival of OSCC patients. Gene Set Enrichment Analysis showed that the higher S100A13 expression group had elevated genes enriched in DNA repair and oxidative phosphorylation. S100A13knockdown increased cisplatin sensitivity, while its overexpression decreased the sensitivity of CAL-27 and SCC-4 cells. S100A13gene had complex alternative transcription patterns. ENST00000440685 is one of the major protein-coding transcripts and was the only transcript elevated in the tumor group. TEAD4 could bind to the promoter of ENST00000440685 and increase its transcription. TEAD4 overexpression alleviated the tumor-suppressive effect of cisplatin in terms of colony formation, the expression of apoptotic proteins, and DNA damage. However, S100A13knockdown partly abrogated the protective effects of TEAD4 overexpression. This study revealed a novel TEAD4-S100A13 axis that might modulate cisplatin sensitivity of OSCC tumor cells.

Characterization of Extracellular Vesicle Cargo in Sjögren's Syndrome through a SWATH-MS Proteomics Approach.

Primary Sjögren’s syndrome (pSS) is a complex heterogeneous disease characterized by a wide spectrum of glandular and extra-glandular manifestations. In this pilot study, a SWATH-MS approach was used to monitor extracellular vesicles-enriched saliva (EVs) sub-proteome in pSS patients, to compare it with whole saliva (WS) proteome, and assess differential expressed proteins between pSS and healthy control EVs samples. Comparison between EVs and WS led to the characterization of compartment-specific proteins with a moderate degree of overlap. A total of 290 proteins were identified and quantified in EVs from healthy and pSS patients. Among those, 121 proteins were found to be differentially expressed in pSS, 82% were found to be upregulated, and 18% downregulated in pSS samples. The most representative functional pathways associated to the protein networks were related to immune-innate response, including several members of S100 protein family, annexin A2, resistin, serpin peptidase inhibitors, azurocidin, and CD14 monocyte differentiation antigen. Our results highlight the usefulness of EVs for the discovery of novel salivary-omic biomarkers and open novel perspectives in pSS for the identification of proteins of clinical relevance that could be used not only for the disease diagnosis but also to improve patients’ stratification and treatment-monitoring. Data are available via ProteomeXchange with identifier PXD025649.

Comprehensive Analysis of the Prognosis and Correlations With Immune Infiltration of S100 Protein Family Members in Hepatocellular Carcinoma.

S100 protein family members (S100s) are commonly dysregulated in various tumors including hepatocellular carcinoma (HCC). However, the diverse expression, mutation, prognosis and associations with immune infiltration of S100s in HCC have yet to be analyzed. Herein we investigated the roles of S100s in HCC from the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), Human Protein Atlas, Kaplan-Meier Plotter, cBioPortal and TIMER databases. Compared with para-cancer tissues, the expression levels of S100A4/S100A6/S100A10/S100A11/S100A13/S100A14/S100P were higher in HCC tissues, while the expression levels of S100A8/S100A9/S100A12 were decreased in tumor tissues. The mRNA levels of S100A2/S100A7/S100A7A/S100A8/S100A9/S100A11 were correlated with advanced tumor stage. Besides, higher mRNA expressions of S100A6/S100A10/S100A11/S100A13/S100A14/S100P were shown to have shorter overall survival (OS), while higher expression of S100A12 was associated with favorable OS. Further, the mutation rate of S100s was investigated, and the high mutation rate (53%) was associated with shorter OS. Additionally, the expressions of S100s were found to be significantly associated with various immune infiltrating cells. Hence, our results showed that S100A6/S100A10/S100A11/S10012/S100A13/S100A14/S100P may be regarded as new prognostic or therapeutic markers and S100s inhibitors may be helpful in the combination of immunotherapies.

Expression Profile of S100A2 and its Clinicopathological Significance in Renal Cell Carcinoma.

Dysregulated expression of S100 protein family members, including S100A2, has been reported in various types of human malignant tumors; however, the functional role of S100A2 in renal cell carcinoma (RCC) remains unknown. The objective of this study was to assess the S100A2 expression pattern and its clinicopathological significance in RCC. This study investigated the expression profiles of S100A2 mRNA, S100A2 protein and p53 mRNA in addition to S100A2 DNA methylation levels in 3 human RCC cell lines and 81 surgically resected RCC specimens. These findings were analyzed according to several clinicopathological parameters. In all RCC cell lines, both S100A2 mRNA and protein were barely detectable, and the S100A2 promoter was considered to be methylated. S100A2 mRNA expression levels in RCC tissues were markedly lower than those in normal kidney tissues. The rate in clear cell RCC (ccRCC) specimens with higher expression of S100A2 mRNA was significantly lower than that in non-ccRCC specimens (29.9 versus 71.4%, respectively). Furthermore, S100A2 expression in ccRCC specimens was significantly correlated with p53 mRNA expression, but not conventional clinicopathological parameters. These findings suggest limited roles of S100A2 in the progression of RCC, particularly ccRCC.

S100A4 is elevated in axial spondyloarthritis: a potential link to disease severity

BackgroundS100A4 is a member of calcium binding S100 protein family well known for its role in cancer progression and metastasis. Nevertheless, S100A4 also serves as a negative regulator of bone formation. Dickkopf-1 (DKK-1), marker of bone remodelling, is also implicated in the process of syndesmophyte formation in ankylosing spondylitis. The aim of our study was to evaluate plasma levels of S100A4 in patients with axial spondyloarthritis and to determine the potential association of S100A4 with disease severity, clinical manifestations and with bone changes in a cross-sectional study.MethodsFifty-eight patients with axial spondyloarthritis and 40 healthy controls were studied. Biological samples were analysed for S100A4 and Dickkopf-1. Disease activity was assessed according to the Bath Ankylosing Spondylitis Disease Activity Index. C-reactive protein (CRP) was used as a marker of inflammation. Radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS).ResultsThe plasma levels of S100A4 were significantly higher in patients with axial spondyloarthritis compared to heathy controls (p < 0.0001). The levels of S100A4 were higher in early stages of the disease and lower in patients with the presence of syndesmophytes (p = 0.009). Furthermore, we found weak but significant inverse correlation of plasma S100A4 with the mSASSS (r = − 0.363, p = 0.030). Levels of S100A4 were negatively associated with disease duration (r = − 0.404, p = 0.002) and positively with Dickkopf-1 binding capacity (r = 0.312, p = 0.023).ConclusionsThis is the first study showing elevated circulating levels of S100A4 in patients with axial spondyloarthritis, particularly in early stages of the disease prior to spinal involvement, and its significantly lower levels in patients with syndesmophytes. The role of S100A4 in the pathogenesis of axial spondyloarthritis can be suggested.

S100A6 is a positive regulator of PPP5C-FKBP51-dependent regulation of endothelial calcium signaling.

ISOC is a cation current permeating the ISOC channel. In pulmonary endothelial cells, ISOC activation leads to formation of inter-endothelial cell gaps and barrier disruption. The immunophilin FK506-binding protein 51 (FKBP51), in conjunction with the serine/threonine protein phosphatase 5C (PPP5C), inhibits ISOC . Free PPP5C assumes an autoinhibitory state, which has low "basal" catalytic activity. Several S100 protein family members bind PPP5C increasing PPP5C catalytic activity in vitro. One of these family members, S100A6, exhibits a calcium-dependent translocation to the plasma membrane. The goal of this study was to determine whether S100A6 activates PPP5C in pulmonary endothelial cells and contributes to ISOC inhibition by the PPP5C-FKBP51 axis. We observed that S100A6 activates PPP5C to dephosphorylate tau T231. Following ISOC activation, cytosolic S100A6 translocates to the plasma membrane and interacts with the TRPC4 subunit of the ISOC channel. Global calcium entry and ISOC are decreased by S100A6 in a PPP5C-dependent manner and by FKBP51 in a S100A6-dependent manner. Further, calcium entry-induced endothelial barrier disruption is decreased by S100A6 dependent upon PPP5C, and by FKBP51 dependent upon S100A6. Overall, these data reveal that S100A6 plays a key role in the PPP5C-FKBP51 axis to inhibit ISOC and protect the endothelial barrier against calcium entry-induced disruption.

Expression profile and functional role of S100A14 in human cancer.

S100A14 is one of the new members of the multi-functional S100 protein family. Expression of S100A14 is highly heterogeneous among normal human tissues, suggesting that the regulation of S100A14 expression and its function may be tissue- and context-specific. Compared to the normal counterparts, S100A14 mRNA and protein levels have been found to be deregulated in several cancer types, indicating a functional link between S100A14 and malignancies. Accordingly, S100A14 is functionally linked with a number of key signaling molecules such as p53, p21, MMP1, MMP9, MMP13, RAGE, NF-kB, JunB, actin and HER2. Of interest, S100A14 seems to have seemingly opposite functions in malignancies arising from the gastrointestional tract (tissues rich in epithelial components) compared to cancers in the other parts of the body (tissues rich in mesenchymal components). The underlying mechanism for these observations are currently unclear and may be related to the relative abundance and differences in the type of interaction partners (effector protein) in different cancer types and tissues. In addition, several studies indicate that the expression pattern of S100A14 has a potential to be clinically useful as prognostic biomarker in several cancer types. This review attempts to provide a comprehensive summary on the expression pattern and functional roles/related molecular pathways in different cancer types. Additionally, the prognostic potential of S100A14 in the management of human malignancies will be discussed.

Ultraviolet B irradiation increases the expression of trichohyalin-like 1 protein in human skin xenotransplants.

Trichohyalin-like (TCHHL)1 is a member of the fused-type S100 protein family. Its function remains unknown, although it has been reported to be expressed in the basal layer of the normal epidermis. The aim of this study was to investigate the effects of ultraviolet B (UVB) irradiation on the expression of TCHHL1 in human skin xenotransplants. Expression of TCHHL1 mRNA was increased in the UVB-exposed skin 2 days after UVB irradiation. TCHHL1 was immunohistochemically detected in the basal layers after sham irradiation. However, on Day 2 after irradiation, the TCHHL1 signals were spread throughout the basal and spinous layers of the irradiated skin, with increased expression of cytokeratin 14 and a dramatic increase in the number of Ki67-positive cells observed. These results show that TCHHL1 is a novel protein whose expression can be increased by UVB irradiation. In addition, this study experimentally shows that TCHHL1 is expressed in proliferative keratinocytes.

S100 proteins as therapeutic targets.

The human genome codes for 21 S100 protein family members, which exhibit cell- and tissue-specific expression patterns. Despite sharing a high degree of sequence and structural similarity, the S100 proteins bind a diverse range of protein targets and contribute to a broad array of intracellular and extracellular functions. Consequently, the S100 proteins regulate multiple cellular processes such as proliferation, migration and/or invasion, and differentiation, and play important roles in a variety of cancers, autoimmune diseases, and chronic inflammatory disorders. This review focuses on the development of S100 neutralizing antibodies and small molecule inhibitors and their potential therapeutic use in controlling disease progression and severity.

High expression of S100A12 on intratumoral stroma cells indicates poor prognosis following surgical resection of hepatocellular carcinoma.

The S100 protein family is widely involved in the pathological process of various types of cancer. However, the prognostic value of the S100 protein family member S100A12 in hepatocellular carcinoma (HCC) remains unknown. A total of 139 patients undergoing curative surgical resection for HCC from December 2005 to June 2006 were investigated. Immunohistochemistry of S100A12 tissue was performed and expression was classified according to the total positive staining area. Co-expression of S100A12 with cluster of differentiation (CD)11B, CD15 and CD68 was evaluated using immunofluorescence. Associations between S100A12 expression and preoperative clinicopathological parameters were assessed using a χ2 test or independent sample Student's t-test. Kaplan-Meier estimator survival analysis and multivariate Cox's proportional hazard regression model were used to evaluate the prognostic value of S100A12 expression. The expression of S100A12 was restricted exclusively to stroma cells, primarily to myeloid-derived immune cells, CD15-positive neutrophils and CD68-positive macrophages in particular. A total positive staining area of 1,600 µm2 was selected as the threshold between high and low S100A12 expression. There was a statistically significant association between intratumoral S100A12 expression and tumor differentiation (P=0.010). High expression of S100A12 on intratumoral stroma cells was an independent prognostic factor for the overall (P=0.002) and disease-free survival (P=0.007) rates of HCC following curative surgical resection. No significant association was identified between peritumoral S100A12 expression and HCC prognosis. The results of the present study demonstrated that high expression of S100A12 on intratumoral stroma cells is associated with poor HCC prognosis following curative resection, which may serve as a potential target for an adjuvant therapy.

Correlation between S100A11 and the TGF-β1/SMAD4 pathway and its effects on the proliferation and apoptosis of pancreatic cancer cell line PANC-1.

S100A11 as a S100 protein family member has been documented to play dual-direction regulation over cancer cell proliferation. We explored the role of S100A11 in the proliferation and apoptosis of pancreatic cancer cell line PANC-1 and the potential mechanisms involving the TGF-β1/SMAD4/p21 pathway. S100A11 and TGF-β1 protein expressions in 30 paraffin-embedded specimens were evaluated by immunohistochemistry. S100A11 and TGF-β1 expression in PANC-1 cell line was suppressed using small interfering RNA (siRNA), respectively. Subsequently, pancreatic cancer cell apoptosis was measured by Cell Counting Kit-8 and flow cytometry, and S100A11 and TGF-β1/SMAD4/p21 pathway proteins and genes were detected with Western blotting and quantitative polymerase chain reaction (qPCR). S100A11 cytoplasmic/nuclear protein translocation was examined using NE-PER® cytoplasm/nuclear protein extraction in cells interfered with TGF-β1 siRNA. Our results showed that S100A11 expression was positively correlated with TGF-β1 expression in pancreatic cancerous tissue. Silencing TGF-β1 down-regulated intracellular P21WAF1 expression by 90%, blocked S100A11 from cytoplasm entering nucleus, and enhanced cell proliferation. Silencing S100A11 down-regulated intracellular P21 expression and promoted cell apoptosis without significantly changing TGF-β1 and SMAD4 expression. Our findings revealed that S100A11 and TGF-β1/SMAD4 signaling pathway were related but mutually independent in regulating PANC-1 cells proliferation and apoptosis. Other independent mechanisms might be involved in S100A11's regulation of pancreatic cell growth. S100A11 could be a potential gene therapy target for pancreatic cancer.

Extracellular S100A9 Protein in Bone Marrow Supports Multiple Myeloma Survival by Stimulating Angiogenesis and Cytokine Secretion.

Dysregulated expression of S100 protein family members is associated with cancer proliferation, invasion, angiogenesis, and inflammation. S100A9 induces myeloid-derived suppressor cell (MDSC) accumulation and activity. MDSCs, immunosuppressive cells that contribute to tumor immune escape, are the main producers of S100A9. In this study, we evaluated the role of extracellular S100A9 and the therapeutic relevance of S100A9 inhibition in multiple myeloma (MM), using the immunocompetent murine 5T33MM model. We demonstrated the presence of S100A9 and its receptor TLR4 in both monocytic and granulocytic MDSCs in human and mouse samples. We showed that S100A9 acted as a chemoattractant for MM cells and induced MDSCs to express and secrete inflammatory and pro-myeloma cytokines, including TNFα, IL6, and IL10. Blocking S100A9 interactions in vivo with the small molecule ABR-238901 did not directly affect MDSC accumulation but did reduce IL6 and IL10 cytokine expression by MDSC. ABR-238901 treatment in vivo reduced angiogenesis but had only minor effects on tumor load as single agent (6% reduction). However, ABR-238901 treatment in combination with bortezomib resulted in an increased reduction in tumor load compared with single treatments (50% relative reduction compared with bortezomib alone). Our data suggest that extracellular S100A9 promotes MM and that inhibition of S100A9 may have therapeutic benefit. Cancer Immunol Res; 5(10); 839-46. ©2017 AACR.

Rho-kinase inhibitor Y-27632 and hypoxia synergistically enhance chondrocytic phenotype and modify S100 protein profiles in human chondrosarcoma cells

Articular chondrocytes are slowly dividing cells that tend to lose their cell type-specific phenotype and ability to produce structurally and functionally correct cartilage tissue when cultured. Thus, culture conditions, which enhance the maintenance of chondrocyte phenotype would be very useful for cartilage research. Here we show that Rho-kinase inhibition by Y-27632 under hypoxic conditions efficiently maintains and even enhances chondrocyte-specific extracellular matrix production by chondrocytic cells. The effects of long-term Y-27632 exposure to human chondrosarcoma 2/8 cell phenotype maintenance and extracellular matrix production were studied at normoxia and at a 5% low oxygen atmosphere. Y-27632 treatment at normoxia induced ACAN and COL2A1 gene up-regulation and a minor increase of sulfated glycosaminoglycans (sGAGs), while type II collagen expression was not significantly up-regulated. A further increase in expression of ACAN and COL2A1 was achieved with Y-27632 treatment and hypoxia. The production of sGAGs increased by 65.8%, and ELISA analysis revealed a 6-fold up-regulation of type II collagen. Y-27632 also induced the up-regulation of S100-A1 and S100-B proteins and modified the expression of several other S100 protein family members, such as S100-A4, S100-A6, S100-A13 and S100-A16. The up-regulation of S100-A1 and S100-B proteins is suggested to enhance the chondrocytic phenotype of these cells.

S100A11 regulates renal carcinoma cell proliferation, invasion, and migration via the EGFR/Akt signaling pathway and E-cadherin.

S100A11 is a S100 protein family member that contributes to cancer progression. Upregulated in human renal cancer tissues, S100A11 may be a prognostic marker for clear cell renal cell carcinoma, but how it functions in cancer is uncertain. Thus, we studied S100A11 and noted knockdown of S100A11 using short hairpin RNA, which inhibited proliferation, invasion, and migration of renal carcinoma cells as well as increased expression of E-cadherin and decreased expression of epidermal growth factor receptor/Akt in renal carcinoma cells. Therefore, S100A11 may be a key molecular target for treating renal carcinoma.

Extracellular S100A4 negatively regulates osteoblast function by activating the NF-κB pathway

Patients with inflammatory bone disease or cancer exhibit an increased risk of fractures and delayed bone healing. The S100A4 protein is a member of the calcium-binding S100 protein family, which is abundantly expressed in inflammatory diseases and cancers. We investigated the effects of extracellular S100A4 on osteoblasts, which are cells responsible for bone formation. Treating primary calvarial osteoblasts with recombinant S100A4 resulted in matrix mineralization reductions. The expression of osteoblast marker genes including osteocalcin and osterix was also suppressed. Interestingly, S100A4 stimulated the nuclear factor-kappaB (NF-κB) signaling pathway in osteoblasts. More importantly, the ex vivo organ culture of mouse calvariae with recombinant S100A4 decreased the expression levels of osteocalcin, supporting the results of our in vitro experiments. This suggests that extracellular S100A4 is important for the regulation of bone formation by activating the NF-κB signaling pathway in osteoblasts.