OBJECTIVE: Exhibiting high consistence in sequence and structure, S100 family members are interchangeable in function and they show a wide spectrum of biological processes, including proliferation, apoptosis, migration, inflammation and differentiation and the like. While the prognostic value of each individual S100 in ovarian cancer is still elusive. In current study, we investigated the prognostic value of S100 family members in the ovarian cancer.
METHODS: We used the Kaplan Meier plotter (KM plotter) database, in which updated gene expression data and survival information are from 1657 ovarian cancer patients, to assess the relevance of individual S100 family mRNA expression to overall survival in various ovarian cancer subtypes and different clinicopathological features.
RESULTS: It was found that high expression of S100A2 (HR = 1.18, 95%CI: 1.04-1.34, P = 0.012), S100A7A (HR = 1.3, 95%CI: 1.04-1.63, P = 0.02),S100A10 (HR = 1.2, 95%CI: 1.05-1.38, P = 0.0087),and S100A16 (HR = 1.23, 95%CI: 1-1.51, P = 0.052) were significantly correlated with worse OS in all ovarian cancer patients, while the expression of S100A1 (HR = 0.87, 95%CI: 0.77-0.99, P = 0.039), S100A3 (HR = 0.83, 95%CI: 0.71-0.96, P = 0.0011), S100A5 (HR = 0.84, 95%CI: 0.73-0.97, P = 0.017), S100A6 (HR = 0.84, 95%CI: 0.72-0.98, P = 0.024), S100A13 (HR = 0.85, 95%CI:0.75-0.97, P = 0.014) and S100G (HR = 0.86, 95%CI: 0.74-0.99, P = 0.041) were associated with better prognosis. Furthermore, we assessed the prognostic value of S100 expression in different subtypes and the clinicopathological features, including pathological grades, clinical stages and TP53 mutation status, of ovarian cancer patients.
CONCLUSION: Comprehensive understanding of the S100 family members may have guiding significance for the diagnosis and outcome of ovarian cancer patients.

BACKGROUND: The S100 protein family is implicated in tumor invasion and metastasis, but its prognostic roles in gastric cancer (GC) has not been elucidated.
MATERIALS AND METHODS: In the current study, Kaplan-Meier plotter (KM plotter) database integrated the expression data and survival information of 1065 GC patients were downloaded from the Gene Expression Omnibus (GEO) (GSE22377, GSE14210 and GSE51105) that published by the three major cancer centers (Berlin, Bethesda and Melbourne). Then this database was used to explore the prognostic values of mRNA expression of each individual S100 in GC patients. We further assessed the prognostic value of S100 in different Lauren classifications, clinicopathological features and clinical treatment of gastric cancer.
RESULTS: Expression of 12 members of the S100 family correlated with overall survival (OS) for all GC patients. Increased expression of S100A3, S100A5, S100A7, S100A7A, S100A11, S100A13, S100Z and S100 G were found to be strongly associated with worse survival, while S100A8, S100A9, S100B and S100 P were correlated with better prognosis in all GC patients. Further assessment of prognostic values of S100 in gastric cancer with different clinical features indicated that different S100 members may interact with different signaling pathways and exerted different functions in gastric cancer development.
CONCLUSIONS: Although the results should be further testified in clinical studies, our findings offer new insights into the contribution of S100 members to GC progression and might promote development of S100 targeted reagents for treating GC.

Low efficiency of chemotherapy in ovarian cancer results from the development of drug resistance. Cisplatin (CIS) and topotecan (TOP) are drugs used in chemotherapy of this cancer. We analyzed the development of CIS and TOP resistance in ovarian cancer cell lines. Incubation of drug sensitive cell lines (W1 and A2780) with cytostatic drugs was used to determine the primary response to CIS and TOP. Quantitative polymerase chain reaction (Q-PCR) was performed to measure the expression levels of the genes. We observed decreased expression of the

PURPOSE: The present study is to discover a new genes associated with drug resistance development in ovarian cancer.
METHODS: We used microarray analysis to determine alterations in the level of expression of genes in cisplatin- (CisPt), doxorubicin- (Dox), topotecan- (Top), and paclitaxel- (Pac) resistant variants of W1 and A2780 ovarian cancer cell lines. Immunohistochemistry assay was used to determine protein expression in ovarian cancer patients.
RESULTS: We observed alterations in the expression of 22 genes that were common to all three cell lines that were resistant to the same cytostatic drug. The level of expression of 13 genes was upregulated and that of nine genes was downregulated. In the CisPt-resistant cell line, we observed downregulated expression of ABCC6, BST2, ERAP2 and MCTP1; in the Pac-resistant cell line, we observe upregulated expression of ABCB1, EPHA7 and RUNDC3B and downregulated expression of LIPG, MCTP1, NSBP1, PCDH9, PTPRK and SEMA3A. The expression levels of three genes, ABCB1, ABCB4 and IFI16, were upregulated in the Dox-resistant cell lines. In the Top-resistant cell lines, we observed increased expression levels of ABCG2, HERC5, IFIH1, MYOT, S100A3, SAMD4A, SPP1 and TGFBI and decreased expression levels of MCTP1 and PTPRK. The expression of EPHA7, IFI16, SPP1 and TGFBI was confirmed at protein level in analyzed ovarian cancer patients..
CONCLUSIONS: The expression profiles of the investigated cell lines indicated that new candidate genes are related to the development of resistance to the cytostatic drugs that are used in first- and second-line chemotherapy of ovarian cancer.

Endogenous lectins have the capacity to translate glycan-encoded information on the cell surface into effects on cell growth. As test cases to examine changes in protein presence associated with tumor growth inhibition, we applied SILAC-based proteomics on human colon carcinoma cells treated with galectin-4 (Gal-4). The five tested lines-LS 180, Vaco 432, Colo 205, CX 1, and HCT 116-responded with differentiation and reduced proliferation to Gal-4 binding. In proteomic analysis (mass spectral data deposited with PRIDE, PXD003489), 2654 proteins were quantified, of which 190 were down-regulated and 115 were up-regulated (>2-fold). 1D annotation analysis of the results indicated down-regulation of DNA replication-associated processes, while protein presence for secretory and transport functions appeared increased. The strongest induction was found for CALB2 (calretinin; ∼24-fold), TGM2 (protein-glutamine γ-glutamyltransferase 2; ∼11-fold), S100A3 (∼10-fold), and GSN (gelsolin; 9.5-fold), and the most pronounced decreases were seen for CDKN2A (tumor suppressor ARF; ∼6-fold), EPCAM (epithelial cell adhesion molecule; ∼6-fold), UBE2C (ubiquitin-conjugating enzyme E2 C; ∼5-fold), KIF2C (kinesin-like protein KIF2C; 5-fold), and LMNB1 (lamin-B1; ∼5-fold). The presence of the common proliferation marker Ki-67 was diminished about 4-fold. By tracing significant alterations of protein expression likely relevant for the observed phenotypic effects, the capacity of a galectin to affect the proteome of human colon cancer cells at multiple sites is revealed.

Epidermal differentiation complex (EDC) comprises a number of genes associated with human skin diseases including psoriasis, atopic dermatitis and hyperkeratosis. These genes have also been linked to numerous cancers, among them skin, gastric, colorectal, lung, ovarian and renal carcinomas. The involvement of EDC components encoding S100 proteins, small proline-rich proteins (SPRRs) and other genes in the tumorigenesis of head and neck squamous cell cancer (HNSCC) has been previously suggested. The aim of the study was to systematically analyze the expression of EDC components on the transcript level in HNSCC. Tissue specimens from 93 patients with HNC of oral cavity and 87 samples from adjacent or distant grossly normal oral mucosawere analyzed. 48 samples (24 tumor and 24 corresponding surrounding tissue) were hybridized to Affymetrix GeneChip Human 1.0 ST Arrays. For validation by quantitative real-time PCR (QPCR) the total RNA from all180 samples collected in the study was analyzed with Real-Time PCR system and fluorescent amplicon specific-probes. Additional set of samples from 14 patients with laryngeal carcinoma previously obtained by HG-U133 Plus 2.0 microarray was also included in the analyses. The expression of analyzed EDC genes was heterogeneous. Two transcripts (S100A1 and S100A4) were significantly down-regulated in oral cancer when compared to normal mucosa (0.69 and 0.36-fold change, respectively), showing an opposite pattern of expression to the remaining S100 genes. Significant up-regulation in tumors was found for S100A11, S100A7, LCE3D, S100A3 and S100A2 genes. The increased expression of S100A7 was subsequently validated by QPCR, confirming significant differences. The remaining EDC genes, including all encoding SPRR molecules, did not show any differences between oral cancer and normal mucosa. The observed differences were also assessed in the independent set of laryngeal cancer samples, confirming the role of S100A3 and LCE3D transcripts in HNC. In HNC of oral cavity only one family of EDC genes (S100 proteins) showed significant cancer-related differences. A number of other transcripts which showed altered expression in HNC require further validation.

Genomic alterations such as chromosomal amplifications, deletions and loss of heterozygosity play an important role in the pathogenesis and progression of cancer. Environmental risk factors contribute to the development and progression of tumors by facilitating the loss of tumor suppressor genes and amplification of oncogenes. In this current study, Affymetrix 10K single nucleotide polymorphism (SNP) arrays were used to evaluate genomic alterations in 20 pairs of matched germ-line and tumor DNA obtained from patients with esophageal squamous cell carcinoma (ESCC) from high-risk area of India where tobacco, betel quid and alcohol use are widespread. Twenty-two amplified regions and 16 deleted regions identified across chromosomal arms were biologically relevant. The candidate genes located at amplified regions of chromosomes or low-level gain regions such as PLA2G5 (1p36-p34), COL11A1 (1p21), KCNK2 (1q41), S100A3 (1q21), ENAH (1q42.12), RGS1 (1q31), KCNH1 (1q32-q41), INSIG2 (2q14.1), FGF12 (3q28), TRIO (5p15.2), RNASEN (5p15.2), FGF10 (5p13-p12), EDN1(6p24.1-p22.3), SULF1 (8q13.2-13.3), TLR4 (9q32-q33), TNC (9q33), NTRK2 (9q22.1), CD44 (11p13), NCAM1 (11q23.1), TRIM29 (11q22-q23), PAK1 (11q13-q14) and RAB27A (15q15-q21.1), are found to be associated with cellular migration and proliferation, tumor cell metastasis and invasion, anchorage independent growth and inhibition of apoptosis. The candidate genes located at deleted regions of chromosomes, such as FBLN2 (3p25.1), WNT7A (3p25), DLC1 (8p22), LZTS1 (8p22), CDKN2A (9p21), COL4A1 (13q34), CDK8 (13q12) and DCC (18q21.3), are found to be associated with the suppression of tumor. The suggested candidate genes were mostly involved in potential signaling pathways such as focal adhesion (COL4A1), tight junction (CLDN10), MAPK signaling pathway (FGF12) and neuroactive ligand receptor interaction pathway (CCKAR). Expression of FGF12 and COL4A1 was validated by tissue microarray. These unique copy number alteration profiles should be taken into consideration when developing biomarkers for the early detection of ESCC in high-risk areas of India in association with tobacco and betel quid use.

BACKGROUND: The S100 protein family comprises 22 members whose protein sequences encompass at least one EF-hand Ca2+ binding motif. They were involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. However, the expression status of S100 family members in gastric cancer was not known yet.
METHODS: Combined with analysis of series analysis of gene expression, virtual Northern blot and microarray data, the expression levels of S100 family members in normal and malignant stomach tissues were systematically investigated. The expression of S100A3 was further evaluated by quantitative RT-PCR.
RESULTS: At least 5 S100 genes were found to be upregulated in gastric cancer by in silico analysis. Among them, four genes, including S100A2, S100A4, S100A7 and S100A10, were reported to overexpressed in gastric cancer previously. The expression of S100A3 in eighty patients of gastric cancer was further examined. The results showed that the mean expression levels of S100A3 in gastric cancer tissues were 2.5 times as high as in adjacent non-tumorous tissues. S100A3 expression was correlated with tumor differentiation and TNM (Tumor-Node-Metastasis) stage of gastric cancer, which was relatively highly expressed in poorly differentiated and advanced gastric cancer tissues (P < 0.05).
CONCLUSION: To our knowledge this is the first report of systematic evaluation of S100 gene expressions in gastric cancers by multiple in silico analysis. The results indicated that overexpression of S100 gene family members were characteristics of gastric cancers and S100A3 might play important roles in differentiation and progression of gastric cancer.

The S100 proteins act as multifactional signaling factors that are involved in the regulation of diverse cellular processes. To explore the involvement of S100 genes in bladder cancers, S100 gene expressions were systematically evaluated at the RNA level by microarray and real-time PCR. Total RNAs were obtained from 4-hydroxybutyl(butyl)nitrosamine (OH-BBN)-induced mouse and rat bladder cancers, human bladder cancers and matched normal bladder urothelium. Microarray analysis was performed on mouse and rat bladder cancers; real-time PCR was performed in mouse, rat and human bladder cancers and their matched normal urothelium for confirmation. Microarray analysis revealed that 9 and 6 members of the S100 gene family were differentially expressed in mouse and rat bladder cancers, respectively. Thirteen members of the S100 gene family were confirmed by real-time PCR to be differentially expressed in human bladder cancers, with overexpression of S100A2, S100A3, S100A5, S100A7, S100A8, S100A9, S100A14, S100A15, S100A16 and S100P, and underexpression of S100A1, S100A4 and S100B. S100A1, S10OA3, S100A8, S10A9, S100A14, S100A15 and S100A16 showed similar patterns of differential expression in bladder cancers from mouse, rat and human. To our knowledge this is the first report of systematic evaluation of S100 gene expressions in bladder cancers. Our results indicate that differential expression of S100 gene family members is characteristic of bladder cancers and these genes may play important roles in bladder tumorigenesis and progression.

Inflammatory cytokines such as interleukin-1 and tumor necrosis factor-alpha modulate a transcription factor cascade in the liver to induce and sustain an acute and systemic defense against foreign entities. The transcription factors involved include NF-kappaB, STAT, and CCAAT/enhancer-binding protein (C/EBP). Whether the NFAT group of transcription factors (which was first characterized as playing an important role in cytokine gene expression in the adaptive response in immune cells) participates in the acute-phase response in hepatocytes is not known. Here, we have investigated whether NFAT is part of the transcription factor cascade in hepatocytes during inflammatory stress. We report that interleukin-1 or tumor necrosis factor-alpha increases expression of and activates NFATc2. C/EBP-mediated NFATc2 induction is temporally required for expression of type IIA secretory phospholipase A2. NFATc2 is also required for expression of phospholipase D1 and the calcium-binding protein S100A3. Thus, a C/EBP-NFATc2 transcription factor cascade provides an additional means to modulate the acute-phase response upon stimulation with inflammatory cytokines.

BACKGROUND: Phospholipase C beta 3 (PLCB3) plays an important role in the signal transduction of the seven transmembrane receptors. The gene is located in the vicinity of the Multiple Endocrine Neoplasia type 1 (MEN1) gene on chromosome 11q13. Transfection of PLCB3 to neuroendocrine cell lines lacking expression suppresses the neoplastic phenotype and affects the gene expression of S100A3 and human mismatch repair protein, suggesting a role for PLCB3 in neuroendocrine tumorigenesis.
MATERIALS AND METHODS: We used RNA-RNA in situ hybridisation for PLCB3 on a total of 82 samples including 34 from MEN1 patients.
RESULTS: We show that the PLCB3 transcript is missing in 8 out of 14 MEN1-associated neoplasias as well as in 4 out of 10 bronchial carcinoids, 2 out of 10 exocrine pancreatic cancers and one sporadic adrenocortical carcinoma.
CONCLUSION: Low or lack of PLCB3 expression in a subset of endocrine tumours, together with earlier published in vitro data on suppressor characteristics upon transfection, indicate that PLCB3 could be involved in the tumorigenesis in a subset of endocrine tumours.

In order to examine whether the expression of calcium-binding proteins of the S100 family may correlate with the transformation grade of human mammary-tumor cells, we studied the expression patterns of 4 members of this family (CACY, CAPL, S100L, S100 alpha/beta) in human breast-cancer cell lines. Each S100 protein is shown to be individually regulated in the human breast-cancer cell lines we studied, but it appears that the expression levels of S100 proteins do not strictly correlate with prognostic factors or the tumorigenicity of the cells. However, 2 aggressive cell lines, MDA-MB-231 and HS-578T, show elevated expression of CAPL. We show that methylation may account for partial regulation of the S100 genes, whereas neither genomic rearrangements in the S100 gene cluster region nor gene dosis effects seem to influence their expression pattern in MDA-MB-231 and MCF-7 cells. On the basis of our genomic analyses, we can localize the gene for S100L within 5 kb upstream of S100E, thus extending the S100 gene cluster by one gene. A series of primary breast tumors was collected and tested for expression of CAPL, CACY and S100 alpha/beta. The results show that all human breast-cancer tissues tested express CACY, whereas the presence of CAPL is more restricted. There is a significant correlation between enhanced expression of CAPL and presence of the invasivity marker urokinase-type plasminogen activator (uPA). This observation suggests that CAPL may play an important role in the acquisition of metastatic potential of human mammary epithelial cells.