Knockdown of S100A2 inhibits the aggressiveness of endometrial cancer by activating STING pathway.

BACKGROUND: Endometrial cancer is a kind of gynaecological cancer. S100A2 is a newfound biomarker to diagnose endometrial cancer. This study was to investigate the role of S100A2 on regulating migration and invasion of endometrial cancer. METHODS: The mRNA and protein levels of S100A2 were obtained by quantitative real-time polymerase chain reaction, immunohistochemistry and western blot methods. Cell viability was measured by the Cell Counting Kit-8 assay. Cell migration and invasion were quantified using transwell assays. Western blot assay was conducted to quantify protein expressions of epithelial to mesenchymal transition-related proteins (N-cadherin and E-cadherin). Furthermore, in vivo tumour formation experiments were performed to evaluate the role of S100A2 on tumour xenografts. RESULTS: S100A2 was significantly up-regulated in endometrial cancer tissues. Knockdown of S100A2 inhibited cell viability, migration and invasion of endometrial cancer cells. Meanwhile, STING pathway was activated by the inhibited S100A2. STING inhibitor C-176 significantly reversed the effects of S100A2 knockdown on aggressive behaviours of endometrial cancer cells. Inhibition of S100A2 dramatically suppresses the tumour growth in vivo. CONCLUSIONS: S100A2 functions as an oncogene in endometrial cancer. Targeting S100A2 may be a promising therapeutic method to treat endometrial carcinoma.

This study was to investigate the role of S100A2 on regulating migration and invasion of endometrial cancer. S100A2 was significantly up-regulated in endometrial cancer tissues. Knockdown of S100A2 inhibited cell viability, migration and invasion of endometrial cancer cells. Meanwhile, STING pathway was activated by the inhibited S100A2. STING inhibitor C-176 significantly reversed the effects of S100A2 knockdown on aggressive behaviours of endometrial cancer cells. Inhibition of S100A2 dramatically suppresses the tumour growth in vivo. S100A2 functions as an oncogene in endometrial cancer. Targeting S100A2 may be a promising therapeutic method to treat endometrial carcinoma.

NFIC1 inhibits the migration and invasion of MDA-MB-231 cells through S100A2-mediated inactivation of MEK/ERK pathway.

NFIC is a potent transcriptional factor involved in many physiological and pathological processes, including tumorigenesis. However, the role of NFIC1, the longest isoform of NFIC, in the progression of triple negative breast cancer (TNBC) remains elusive. Our study demonstrates that overexpression of NFIC1 inhibits the migration and invasion of TNBC MDA-MB-231 cells. NFIC1 regulates the expression of S100A2, and knockdown of S100A2 reverses the inhibitive effects of NFIC1 on the migration and invasion of MDA-MB-231 cells. Furthermore, knockdown of S100A2 activates the MEK/ERK signaling transduction pathway that is inhibited by NFIC1 overexperssion. Treatment with MEK/ERK pathway inhibitor, U0126, abolishes the effects of S100A2 knockdown. In addition, overexpression of NFIC1 in MDA-MB-231 cells increases the expression of epithelial markers and decreases the expression of mesenchymal markers, and these effects could also be reversed by knockdown of S100A2. Collectively, these results demonstrate that NFIC1 inhibits the Epithelial-mesenchymal transition (EMT) of MDA-MB-231 cells by regulating S100A2 expression, which suppress the activation of MEK/ERK pathway. Therefore, our study confirms the role of NFIC1 as a tumor repressor in TNBC, and reveals the molecular mechanism through which NFIC1 inhibits the migration and invasion of MDA-MB-231 cells.

Transcriptional activation of S100A2 expression by HIF-1α via binding to the hypomethylated hypoxia response elements in HCC cells.

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers. Dysregulation of S100A2 has recently been found in many cancers including HCC. However, its regulatory mechanism in HCC remains poorly understood, especially in hypoxia. In this study, we found that S100A2 is upregulated and correlated with the clinicopathological features of HCC patients. Moreover, the elevated S100A2 showed worse overall survival. Functionally, S100A2 inhibition decreased the proliferation and migration of HepG2 cells. Interestingly, we found that HIF-1α directly binds to hypoxia response elements (HREs) of the S100A2 promoter region. S100A2 expression could be induced in an HIF-1α-dependent manner under hypoxia. Furthermore, S100A2 silencing significantly suppressed HCC cell proliferation and invasion under hypoxia. Mechanistically, pyrosequencing results showed that the hypomethylation status of CpG located in the HRE at the S100A2 promoter was correlated with S100A2 induction. Additionally, HIF-1α- mediated S100A2 activation was associated with TET2-related epigenetic inactivation. TET2 was enriched in the HRE of the S100A2 promoter in HepG2 cells. Finally, S100A2 methylation-related genes and pathways were analyzed. We found that the methylation of S100A2 is correlated with ANXA2, PPP1R15A, and FOS, which include in a hypoxia-related gene set from the GSEA database. Moreover, some EMT-related genes are associated with the methylation of S100A2 in HCC. Conclusively, our study thus uncovered a novel mechanism showing that hypoxia/HIF-1α signaling associated with DNA methylation enhances S100A2 expression in HCC. S100A2 may be useful as a target for facilitating novel diagnostic and therapeutic strategies in liver cancer.

High expression of S100A2 predicts poor prognosis in patients with endometrial carcinoma.

BACKGROUND: S100A2, a member of the S100 protein family, is abnormally expressed and plays a vital role in multiple cancers. However, little is known about the clinical significance of S100A2 in endometrial carcinoma. METHODS: Clinicopathological data were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Omnibus (GEO), and Clinical Proteomic Tumor Analysis Consortium (CPTAC). First, the expression and prognostic value of different S100 family members in endometrial carcinoma were evaluated. Subsequently, the Kaplan-Meier plotter and Cox regression analysis were used to assess the prognostic significance of S100A2, while the association between S100A2 expression and clinical characteristics in endometrial carcinoma was also analyzed using logistic regression. A receiver operating characteristic (ROC) curve and a nomogram were constructed. The putative underlying cellular mechanisms were explored using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and gene set enrichment analysis (GSEA). RESULTS: Our results revealed that S100A2 expression was significantly higher in endometrial carcinoma tissue than in non-cancerous tissue at both the mRNA and protein levels. Analysis of Kaplan-Meier plotter data revealed that patients with high S100A2 expression had shorter overall survival (OS) and disease specific survival (DSS) compared with those of patients with low S100A2 expression. Multivariate Cox analysis further confirmed that high S100A2 expression was an independent risk factor for OS in patients with endometrial carcinoma. Other clinicopathologic features found to be related to worse prognosis in endometrial carcinoma included age, clinical stage, histologic grade, and tumor invasion. Importantly, ROC analysis also confirmed that S100A2 has a high diagnostic value in endometrial carcinoma. KEGG enrichment analysis and GSEA revealed that the estrogen and IL-17 signaling pathways were significantly upregulated in the high S100A2 expression group, in which estrogen response, JAK-STAT3, K-Ras, and TNFα/NF-κB were differentially enriched. CONCLUSIONS: S100A2 plays an important role in endometrial carcinoma progression and may represent an independent diagnostic and prognostic biomarker for endometrial carcinoma.

S100A2 promotes glycolysis and proliferation via GLUT1 regulation in colorectal cancer.

The deregulation of S100A2 has been implicated in the pathogenesis of several types of cancers. However, the molecular mechanisms underlying the protumorigenic capacities of S100A2 have not been fully elucidated. Here, we demonstrated the molecular mechanisms underlying the roles of S100A2 in glycolysis reprogramming and proliferation of colorectal cancer (CRC) cells. The results indicated that S100A2 overexpression raises glucose metabolism and proliferation. Mechanistically, S100A2 activated the PI3K/AKT signaling pathway, upregulated GLUT1 expression, induced glycolytic reprogramming, and consequently increased proliferation. Clinical data showed significantly increased S100A2 levels in CRC tissues and the Oncomine database. In addition, analysis revealed a positive correlation between S100A2 and GLUT1 mRNA expression in CRC tissues. Together, these results demonstrate that the S100A2/GLUT1 axis can promote the progression of CRC by modulating glycolytic reprogramming. Our results further suggest that targeting S100A2 could present a promising therapeutic avenue for the prevention of colorectal cancer progression.

Hypoxia and hyperoxia differentially control proliferation of rat neural crest stem cells via distinct regulatory pathways of the HIF1α-CXCR4 and TP53-TPM1 proteins.

BACKGROUND: Neural crest stem cells (NCSCs) are a population of adult multipotent stem cells. We are interested in studying whether oxygen tensions affect the capability of NCSCs to self-renew and repair damaged tissues. NCSCs extracted from the hair follicle bulge region of the rat whisker pad were cultured in vitro under different oxygen tensions. RESULTS: We found significantly increased and decreased rates of cell proliferation in rat NCSCs (rNCSCs) cultured, respectively, at 0.5% and 80% oxygen levels. At 0.5% oxygen, the expression of both hypoxia-inducible factor (HIF) 1α and CXCR4 was greatly enhanced in the rNCSC nuclei and was suppressed by incubation with the CXCR4-specific antagonist AMD3100. In addition, the rate of cell apoptosis in the rNCSCs cultured at 80% oxygen was dramatically increased, associated with increased nuclear expression of TP53, decreased cytoplasmic expression of TPM1 (tropomyosin-1), and increased nuclear-to-cytoplasmic translocation of S100A2. Incubation of rNCSCs with the antioxidant N-acetylcysteine (NAC) overcame the inhibitory effect of 80% oxygen on proliferation and survival of rNCSCs. CONCLUSIONS: Our results show for the first time that extreme oxygen tensions directly control NCSC proliferation differentially via distinct regulatory pathways of proteins, with hypoxia via the HIF1α-CXCR4 pathway and hyperoxia via the TP53-TPM1 pathway. Developmental Dynamics 246:162-185, 2017. © 2016 Wiley Periodicals, Inc.

Diagnostic significance of S100A2 and S100A6 levels in sera of patients with non-small cell lung cancer.

Biochemical markers play a significant role in the diagnosis of lung cancer. Recent studies have demonstrated a link involving S100 Calcium Binding Proteins (S100A2, S100A6) and non-small cell lung cancer (NSCLC), but the expediency of their serum levels in NSCLC has not been established. In this study, we evaluate the potential of serum S100A2 and S100A6 levels as diagnostic markers for NSCLC. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the levels of S100A2 and S100A6 in 141 NSCLC patients and 150 healthy subjects. Serum levels of the two proteins in patients with NSCLC were higher compared to healthy controls (P = 0.0002 for S100A2 and P < 0.0001 for S100A6). Moreover, the levels of S100A2 and S100A6 were higher in the sera of stage I/II NSCLC patients compared to healthy controls with P = 0.01 and <0.0001, respectively. Receiver operating characteristic (ROC) analysis showed that S100A2 could distinguish NSCLC patients from healthy controls (AUC = 0.646), and S100A6 could also identify NSCLC (AUC = 0.668). Meanwhile, these two proteins showed notable capabilities for distinguishing stage I/II NSCLC from healthy controls (AUC = 0.708 for S100A2 and AUC = 0.702 for S100A6). Our results indicate that serum levels of S100A2 and S100A6 are significantly elevated in early stage NSCLC and may have the potential for NSCLC biomarker. Further studies with large sample population would help validate our findings.

Multi-omics Analysis Identifies Hypoxia Subtypes and S100A2 as an Immunosuppressive Factor in Cervical Cancer.

Cervical cancer is a common gynecological oncology. Growing evidence indicates hypoxia plays an important role in tumor progression and immunity. However, no study has examined the hypoxia landscape in cervical cancer. In this study, using hierarchical clustering, we identified three hypoxia subtypes in cervical cancer samples from The Cancer Genome Atlas dataset according to formerly described hypoxia-related genes. The overall survival time, hypoxic features, genomics, and immunological characteristics of these subtypes existed distinct differences. We also created a hypoxia score by principle component analysis for dimension reduction. The hypoxiaScore was an effective prognostic biomarker validated by GSE44001 and was associated with immunotherapy response. Furthermore, combined with single-cell RNA-sequence (scRNA-seq) and experiments, S100A2 was identified as an immunosuppressive factor induced by hypoxia and regulated expression of PD-L1. S100A2 also served as an oncogene promoting the proliferation and migration of cervical cancer cells. These findings depicted a new hypoxia-based classification and identified S100A2 as a potential therapeutic target for cervical cancer, thereby advancing the understanding of immunotherapy resistance mechanisms and cervical cancer genetic markers.

Protein expression of S100A2 reveals it association with patient prognosis and immune infiltration profile in colorectal cancer.

PURPOSE: Colorectal cancer (CRC) is the third most diagnosed cancer worldwide. Despite a well-established knowledge of tumour development, biomarkers to predict patient outcomes are still required. S100 calcium-binding protein A2 (S100A2) has been purposed as a potential marker in many types of cancer, however, the prognostic value of S100A2 in CRC is rarely reported. MATERIAL AND METHODS: In this study, immunohistochemistry (IHC) was performed to identify the prognostic role of S100A2 protein expression in the tumour core of the tissue microarrays (TMAs) in colorectal cancer patients (n=787). Bulk RNA transcriptomic data was used to identify significant genes compared between low and high cytoplasmic S100A2 groups. Multiplex immunofluorescence (mIF) was performed to further study and confirm the immune infiltration in tumours with low and high cytoplasmic S100A2. RESULTS: Low cytoplasmic protein expression of S100A2 in the tumour core was associated with poor survival (HR 0.539, 95%CI 0.394-0.737, P<0.001) and other adverse tumour phenotypes. RNA transcriptomic analysis showed a gene significantly associated with the low cytoplasmic S100A2 group (AKT3, TAGLN, MYLK, FGD6 and ETFDH), which correlated with tumour development and progression. GSEA analysis identifies the enriched anti-tumour and immune activity group of genes in high cytoplasmic S100A2. Additionally, mIF staining showed that high CD3+FOXP3+ and CD163+ inversely associated with low cytoplasmic S100A2 (P<0.001, P=0.009 respectively). CONCLUSION: Our finding demonstrates a prognostic value of S100A2 together with the correlation with immune infiltration in CRC.

LncRNA RP11-93B14.5 promotes gastric cancer cell growth through PI3K/AKT signaling pathway.

OBJECTIVE: Emerging evidence indicates that long non-coding RNA (lncRNA) RP11-93B14.5 facilitates tumor progression in variety of malignancies. The present study proposed to study the functional effect of lncRNA RP11-93B14.5 in gastric cancer (GC) as well as the underlying mechanism. METHODS: Bioinformatics analysis was utilized to analyze lncRNA expression in GC tissues. siRNA was used for knockdown of RP11-93B14.5 in GC cells MKN45 and KATO III. The stable knockdown cell lines were constructed by CRISPR-Cas9. Cell counting kit-8 (CCK-8) assay and soft agar colony formation assay were used to analyze GC cell viability. Flow cytometry analysis was performed to analyze the cell cycle distribution of MKN45 and KATO III. RNA sequencing (RNA-seq) was employed to detect differential genes after transfection with siRP11-93B14.5. Quantitative PCR (Q-PCR) was used to examine gene expression in GC cell lines. Western-blot assay was used to measure protein levels. RNA fluorescent in situ hybridization (FISH) was conducted for lncRNA cellular location and expression. RESULTS: Based on the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database, RP11-93B14.5 was upregulated in GC tissue, which was also verified in GC cell lines in comparison to the normal gastric epithelial HFE145 cells. Knockdown of RP11-93B14.5 decreased cell viability and the colony number of MKN45 and KATO III cells, and altered cell cycle distribution in vitro. RNA-seq analysis revealed RP11-93B14.5 may modulate genes expression of S100A2 and TIMP2 in MKN45 and KATO III cells. Mechanistically, RP11-93B14.5 may drive the progression of GC via S100A2 related-PI3K/AKT signaling pathway. CONCLUSIONS: LncRNA RP11-93B14.5 knockdown alleviated the malignant phenotypes of GC cells through regulating PI3K/AKT. Our results provide evidence for the role of lncRNAs in regulating tumor progression.

Influence of S100A2 in Human Diseases.

S100 proteins are a family of low-molecular-weight proteins characterized by two calcium-binding sites with a helix-loop-helix ("EF-hand-type") domain. The S100 family of proteins is distributed across various organs and can interact with diverse molecules. Among the proteins of the S100 family, S100 calcium-binding protein A2 (S100A2) has been identified in mammary epithelial cells, glands, lungs, kidneys, and prostate gland, exhibiting various physiological and pathological actions in human disorders, such as inflammatory diseases and malignant tumors. In this review, we introduce basic knowledge regarding S100A2 regulatory mechanisms. Although S100A2 is a tumor suppressor, we describe the various influences of S100A2 on cancer and inflammatory diseases.

S100A2: A potential biomarker to differentiate malignant from tuberculous pleural effusion.

BACKGROUND: S100 calcium binding protein A2 (S100A2)-which has been testified to have an abnormal expression in non-small cell lung cancer (NSCLC)-is considered as an effective biomarker in the diagnosis and prognosis of this malignancy. In this study, we detected the S100A2 levels in pleural effusion, aiming to evaluate its potential value in differentiating malignant pleural effusion (MPE) from tuberculous pleural effusion (TPE). METHODS: We collected pleural effusion from 104 NSCLC patients with MPE and 96 tubercular pleurisy cases. Enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of S100A2 in these samples. Meanwhile, the serum S100A2 levels were also examined in same subjects. The data concerning the expression of those commonly-used markers, including CEA, CYFRA211 and NSE, were obtained from medical records. RESULTS: Like other classified biomarkers, S100A2 had an over-expression in both pleural effusion and sera of the NSCLC patients compared with controls (P = 0.000), though having a lower P value. Receiver operating characteristic (ROC) analysis showed that the levels of S100A2 in pleural effusion (PE) could distinguish MPE from tuberculous pleurisy (Area Under the Receiver Operating Characteristic Curve (AUC) = 0.887), and its diagnostic value in hydrothorax was obviously higher than in serum (AUC = 0.709). CONCLUSION: Our results indicate that levels of S100A2 are significantly elevated in MPE, and that S100A2 may serve as a diagnostic biomarker for NSCLC patients with MPE. In further studies, we will validate our findings with a larger sample population.

Development and Verification of a Prostate Cancer Prognostic Signature Based on an Immunogenomic Landscape Analysis.

PURPOSE: Prostate cancer (PCa) has a high incidence among older men. Until now, there are no immunological markers available to predict PCa patients' survival. Therefore, it is necessary to explore the immunological characteristics of PCa. METHODS: First, we retrieved RNA-seq and clinical data of 499 PCa and 52 normal prostate tissue samples from the Cancer Genome Atlas (TCGA). We identified 193 differentially expressed immune-related genes (IRGs) between PCa and normal prostate tissues. Functional enrichment analyses showed that the immune system can participate in PCa initiation. Then, we constructed a correlation network between transcription factors (TFs) and IRGs. We performed univariate and multivariate Cox regression analyses and identified five key prognostic IRGs (S100A2, NOX1, IGHV7-81, AMH, and AGTR1). Finally, a predictive nomogram was established and verified by the C-index. RESULTS: We successfully constructed and validated an immune-related PCa prediction model. The signature could independently predict PCa patients' survival. Results showed that high-immune-risk patients were correlated with advanced stage. We also validated the S100A2 expression in vitro using PCa and normal prostate tissues. We found that higher S100A2 expressions were related to lower biochemical recurrences. Additionally, higher AMH expressions were related to higher Gleason score, lymph node metastasis and positive rate, and tumor stages, and higher ATGR1 expressions were related to lower PSA value. CONCLUSION: Overall, we detected five IRGs (S100A2, NOX1, IGHV7-81, AMH, and AGTR1) that can be used as independent PCa prognostic factors.

Targeting the S100A2-p53 Interaction with a Series of 3,5-Bis(trifluoromethyl)benzene Sulfonamides: Synthesis and Cytotoxicity.

In silico approaches identified 1, N-(6-((4-bromo- benzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of the S100A2-p53 protein-protein interaction, a validated pancreatic cancer drug target. Subsequent cytotoxicity screening revealed it to be a 2.97 µM cell growth inhibitor of the MiaPaCa-2 pancreatic cell line. This is in keeping with our hypothesis that inhibiting this interaction would have an anti-pancreatic cancer effect with S100A2, the validated PC drug target. A combination of focused library synthesis (three libraries, 24 compounds total) and cytotoxicity screening identified a propyl alkyl diamine spacer as optimal; the nature of the terminal phenyl substituent had limited impact on observed cytotoxicity, whereas N-methylation was detrimental to activity. In total 15 human cancer cell lines were examined, with most analogues showing broad-spectrum activity. Near uniform activity was observed against a panel of six pancreatic cancer cell lines: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1. In all cases there was good to excellent correlation between the predicted docking pose in the S100A2-p53 binding groove and the observed cytotoxicity, especially in the pancreatic cancer cell line with high endogenous S100A2 expression. This supports S100A2 as a pancreatic cancer drug target.

S100A2 Silencing Relieves Epithelial-Mesenchymal Transition in Pulmonary Fibrosis by Inhibiting the Wnt/ß-Catenin Signaling Pathway.

Pulmonary fibrosis (PF) is a progressive and lethal disease with poor prognosis. S100A2 plays an important role in the progression of cancer. However, the role of S100A2 in PF has not yet been reported. In this study, we explored the potential role of S100A2 in PF and its potential molecular mechanisms. Increased expression of S100A2 was first observed in lung tissues of PF patients. We found that downregulation of S100A2 inhibited the transforming growth factor-ß1 (TGF-ß1)-induced epithelial-mesenchymal transition (EMT) in A549 cells. Mechanically, TGF-ß1 upregulated ß-catenin and the phosphorylation of glycogen synthase kinase-3ß, which was blocked by silencing S100A2 in vitro. Furthermore, lithium chloride (activator of the Wnt/ß-catenin signaling pathway) effectively rescued S100A2 knockdown-mediated inhibition of EMT in PF. In conclusion, these findings demonstrate that downregulation of S100A2 alleviated PF through inhibiting EMT. S100A2 is a promising potential target for further understanding the mechanism and developing a strategy for the treatment of PF and other EMT-associated diseases.

Cytotoxic 1,2,3-Triazoles as Potential Leads Targeting the S100A2-p53 Complex: Synthesis and Cytotoxicity.

In silico screening predicted 1 (N-(4-((4-(3-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazin-1-yl) sulfonyl)-phenyl)acetamide) as an inhibitor of the S100A2-p53 protein-protein interaction. S100A2 is a validated pancreatic cancer drug target. In the MiaPaCa-2 pancreatic cell line, 1 was a ∼50 µM growth inhibitor. Synthesis of five focused compound libraries and cytotoxicity screening revealed increased activity from the presence of electron withdrawing moieties on the sulfonamide aromatic ring, with the 3,5-bis-CF3 Library 3 analogues the most active, with GI50 values of 0.91 (3-ClPh; 13 i; BxPC-3, Pancreas) to 9.0 µM (4-CH3 ; 13 d; PANC-1, Pancreas). Activity was retained against an expanded pancreatic cancer cell line panel (MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, PANC-1 and HPAC) and the normal cell line MCF10A (breast). Bulky 4-disposed substituents on the terminal phenyl ring enhanced broad spectrum activity with growth inhibition values spanning 1.1 to 3.1 µM (4-C(CH3 )3 ; 13 e; BxPC-3 and AsPC-1 (pancreas), respectively). Central alkyl spacer contraction from propyl to ethyl proved detrimental to activity with Library 4 and 5.5- to 10-fold less cytotoxic than the propyl linked Library 2 and Library 3. The data herein was consistent with the predicted binding poses of the compounds evaluated. The highest levels of cytotoxicity were observed with those analogues best capable of adopting a near identical pose to the p53-peptide in the S100A2-p53 binding groove.

The S100 protein family in lung cancer.

The S100 protein family is involved in the pathogenesis of several malignancies including lung cancer. Recent studies have shown that one member, S100A2, was over-expressed in advanced stage non-small cell lung cancer (NSCLC). Another, S100A6, demonstrated variable expression in different lung cancer subtypes. Research using NSCLC cell lines reported that SIX3 inhibited cell metastasis and proliferation via S100P down-regulation. This review represents an update on S100 proteins in lung cancer from 2017 to 2021 and includes the aforementioned as well as S100A4, S100A7, and S100B. Inconsistencies in mechanisms of action for S100A8/S100A9 are highlighted and a comprehensive evaluation of the most recent evidence for the S100 proteins in lung cancer is presented.

S100A2 Is a Prognostic Biomarker Involved in Immune Infiltration and Predict Immunotherapy Response in Pancreatic Cancer.

Pancreatic cancer (PC) is a highly fatal and aggressive disease with its incidence and mortality quite discouraging. It is of great significance to construct an effective prognostic signature of PC and find the novel biomarker for the optimization of the clinical decision-making. Due to the crucial role of immunity in tumor development, a prognostic model based on nine immune-related genes was constructed, which was proved to be effective in The Cancer Genome Atlas (TCGA) training set, TCGA testing set, TCGA entire set, GSE78229 set, and GSE62452 set. Furthermore, S100A2 (S100 Calcium Binding Protein A2) was identified as the gene occupying the most paramount position in risk model. Gene set enrichment analysis (GSEA), ESTIMATE and CIBERSORT algorithm revealed that S100A2 was closely associated with the immune status in PC microenvironment, mainly related to lower proportion of CD8+T cells and activated NK cells and higher proportion of M0 macrophages. Meanwhile, patients with high S100A2 expression might get more benefit from immunotherapy according to immunophenoscore algorithm. Afterwards, our independent cohort was also used to demonstrate S100A2 was an unfavorable marker of PC, as well as its remarkably positive correlation with the expression of PD-L1. In conclusion, our results demonstrate S100A2 might be responsible for the preservation of immune-suppressive status in PC microenvironment, which was identified with significant potentiality in predicting prognosis and immunotherapy response in PC patients.

Regulation of the tubulin polymerization-promoting protein by Ca2+/S100 proteins.

To elucidate S100 protein-mediated signaling pathways, we attempted to identify novel binding partners for S100A2 by screening protein arrays carrying 19,676 recombinant glutathione S-transferase (GST)-fused human proteins with biotinylated S100A2. Among newly discovered putative S100A2 interactants, including TMLHE, TRH, RPL36, MRPS34, CDR2L, OIP5, and MED29, we identified and characterized the tubulin polymerization-promoting protein (TPPP) as a novel S100A2-binding protein. We confirmed the interaction of TPPP with Ca2+/S100A2 by multiple independent methods, including the protein array method, S100A2 overlay, and pulldown assay in vitro and in transfected COS-7 cells. Based on the results from the S100A2 overlay assay using various GST-TPPP mutants, the S100A2-binding region was identified in the C-terminal (residues 111-160) of the central core domain of a monomeric form of TPPP that is involved in TPPP dimerization. Chemical cross-linking experiments indicated that S100A2 suppresses dimer formation of His-tagged TPPP in a dose-dependent and a Ca2+-dependent manner. In addition to S100A2, TPPP dimerization is disrupted by other multiple S100 proteins, including S100A6 and S100B, in a Ca2+-dependent manner but not by S100A4. This is consistent with the fact that S100A6 and S100B, but not S100A4, are capable of interacting with GST-TPPP in the presence of Ca2+. Considering these results together, TPPP was identified as a novel target for S100A2, and it is a potential binding target for other multiple S100 proteins, including S100A6 and S100B. Direct binding of the S100 proteins with TPPP may cause disassembly of TPPP dimer formation in response to the increasing concentration of intracellular Ca2+, thus resulting in the regulation of the physiological function of TPPP, such as microtubule organization.

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

BACKGROUND/AIM: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: These findings suggest limited roles of S100A2 in the progression of RCC, particularly ccRCC.