S100P

Gene Summary

Gene:S100P; S100 calcium binding protein P
Aliases: MIG9
Location:4p16.1
Summary:The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21; however, this gene is located at 4p16. This protein, in addition to binding Ca2+, also binds Zn2+ and Mg2+. This protein may play a role in the etiology of prostate cancer. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein S100-P
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Latest Publications: S100P (cancer-related)

Jiang H, Hu H, Lin F, et al.
S100P is Overexpressed in Squamous Cell and Adenosquamous Carcinoma Subtypes of Endometrial Cancer and Promotes Cancer Cell Proliferation and Invasion.
Cancer Invest. 2016; 34(10):477-488 [PubMed] Related Publications
S100P is known to affect tumor development and metastasis of various cancers, but its role in endometrial cancer is unclear. We reported that S100P expression was dramatically elevated in both endometrial squamous cell carcinoma and adenosquamous carcinoma, but not in adenocarcinoma and normal endometrial samples. Moreover, we revealed an oncogenic role of S100P promoting cell proliferation, invasion, and migration while reducing apoptosis, possibly via its upregulation and/or activation of receptors of advanced glycation end products and consequently the oncogenic PI3K-AKT and MAPK pathways. Therefore, S100P might be a specific biomarker and a potential drug target for squamous cell and adenosquamous carcinoma subtypes of endometrial cancer.

Shen ZY, Fang Y, Zhen L, et al.
Analysis of the predictive efficiency of S100P on adverse prognosis and the pathogenesis of S100P-mediated invasion and metastasis of colon adenocarcinoma.
Cancer Genet. 2016; 209(4):143-53 [PubMed] Related Publications
Elevated expression of S100P has been detected in several tumor types. To analyze the potential use of S100P for the prediction of colorectal cancer (CRC) metastasis and prognosis, S100P expression was detected in 125 patients with colon adenocarcinoma by immunohistochemistry, followed by correlation and survival analysis. High S100P expression was correlated with metastasis, as demonstrated by clinically relevant data, and predicted poor survival more effectively than preoperative serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels in colon adenocarcinoma. Stable S100P knockdown CRC cell lines were established to elucidate the relationship between S100P expression and tumor progression in vitro and in vivo. S100P knockdown resulted in reductions in the invasiveness and metastasis of CRC cells. Xenograft growth in nude mice also demonstrated that down-regulated S100P dramatically inhibited peritoneal metastasis of CRC cells. S100P promoted the invasion and metastasis of CRC by activating RAGE/ERK signaling and promoting the epithelial-mesenchymal transition (EMT). RAGE was found to be crucial for S100P-mediated EMT in colon cancer. Knockdown of RAGE in S100P-overexpressing colon cancer cells dramatically suppressed EMT process. Our results indicate that overexpression of S100P is related with an invasive and metastatic phenotype of CRC which is EMT-involved and RAGE dependent.

Li Z, Chen Y, Wang X, et al.
LASP-1 induces proliferation, metastasis and cell cycle arrest at the G2/M phase in gallbladder cancer by down-regulating S100P via the PI3K/AKT pathway.
Cancer Lett. 2016; 372(2):239-50 [PubMed] Related Publications
LASP-1 is an actin-binding protein that regulates cytoskeletal dynamics and cell migration. LASP-1 was previously identified in a cDNA library from metastatic breast cancer samples. This protein has since been detected in multiple human cancers, including liver cancer, gastric cancer and pancreatic cancer. S100P is a small calcium-binding protein in the S100 protein family that regulates cellular, physiological and pathological processes in various cancers. However, the clinical significance of LASP-1 and S100P expression in gallbladder cancer (GBC) is not yet clear. In our study, we focused on the clinical significance, biological function and mechanism of LASP-1 in gallbladder cancer and detected LASP-1 and S100P overexpression in GBC tissues. The expression of LASP-1 was significantly correlated with poor prognosis in GBC patients (P < 0.05). Furthermore, down-regulation of LASP-1 expression resulted in the obvious inhibition of proliferation and migration and caused cell cycle arrest by down-regulating S100P via the PI3K/AKT pathway; in mice, tumor volume was significantly decreased. In conclusion, LASP-1 may act as an oncogene to regulate the expression of S100P to influence cellular functions in GBC. LASP-1 could serve as a genetic treatment target in GBC patients.

Tian W, Liu J, Pei B, et al.
Identification of miRNAs and differentially expressed genes in early phase non-small cell lung cancer.
Oncol Rep. 2016; 35(4):2171-6 [PubMed] Related Publications
To explore the potential therapeutic targets of early‑stage non-small cell lung cancer (NSCLC), gene microarray analysis was conducted. The microarray data of NSCLC in stage IA, IB, IIA, and IIB (GSE50081), were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) in IB vs. IA, IIA vs. IB, IIB vs. IIA were screened out via R. ToppGene Suite was used to get the enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the DEGs. The GeneCoDis3 database and Cytoscape software were used to construct the transcriptional regulatory network. In total, 25, 17 and 14 DEGs were identified in IB vs. IA, IIA vs. IB, IIB vs. IIA of NSCLC, respectively. Some GO terms and pathways (e.g., extracellular space, alveolar lamellar body, bioactivation via cytochrome P450 pathway) were found significantly enriched in DEGs. Genes S100P, ALOX15B, CCL11, NLRP2, SERPINA3, FoxO4 and hsa-miR-491 may play important roles in the development of early-stage NSCLC. Thus, by bioinformatics analysis the key genes and biological processes involving in the development of early-stage NSCLC could be established, providing more potential references for the therapeutic targets.

Hu R, Huffman KE, Chu M, et al.
Quantitative Secretomic Analysis Identifies Extracellular Protein Factors That Modulate the Metastatic Phenotype of Non-Small Cell Lung Cancer.
J Proteome Res. 2016; 15(2):477-86 [PubMed] Free Access to Full Article Related Publications
Lung cancer is the leading cause of cancer-related deaths for men and women in the United States, with non-small cell lung cancer (NSCLC) representing 85% of all diagnoses. Late stage detection, metastatic disease and lack of actionable biomarkers contribute to the high mortality rate. Proteins in the extracellular space are known to be critically involved in regulating every stage of the pathogenesis of lung cancer. To investigate the mechanism by which secreted proteins contribute to the pathogenesis of NSCLC, we performed quantitative secretomic analysis of two isogenic NSCLC cell lines (NCI-H1993 and NCI-H2073) and an immortalized human bronchial epithelial cell line (HBEC3-KT) as control. H1993 was derived from a chemo-naïve metastatic tumor, while H2073 was derived from the primary tumor after etoposide/cisplatin therapy. From the conditioned media of these three cell lines, we identified and quantified 2713 proteins, including a series of proteins involved in regulating inflammatory response, programmed cell death and cell motion. Gene Ontology (GO) analysis indicates that a number of proteins overexpressed in H1993 media are involved in biological processes related to cancer metastasis, including cell motion, cell-cell adhesion and cell migration. RNA interference (RNAi)-mediated knock down of a number of these proteins, including SULT2B1, CEACAM5, SPRR3, AGR2, S100P, and S100A14, leads to dramatically reduced migration of these cells. In addition, meta-analysis of survival data indicates NSCLC patients whose tumors express higher levels of several of these secreted proteins, including SULT2B1, CEACAM5, SPRR3, S100P, and S100A14, have a worse prognosis. Collectively, our results provide a potential molecular link between deregulated secretome and NSCLC cell migration/metastasis. In addition, the identification of these aberrantly secreted proteins might facilitate the development of biomarkers for early detection of this devastating disease.

Chen L, Huang K, Himmelfarb EA, et al.
Diagnostic value of maspin in distinguishing adenocarcinoma from benign biliary epithelium on endoscopic bile duct biopsy.
Hum Pathol. 2015; 46(11):1647-54 [PubMed] Related Publications
Histopathologic distinction between benign and malignant epithelia on endoscopic bile duct biopsy can be extremely challenging due to small sample size, crush artifact, and a propensity for marked inflammatory and reactive changes after stent placement. Our previous studies have shown that the insulin-like growth factor II mRNA-binding protein 3, S100P, and the von Hippel-Lindau gene product (pVHL) can help the distinction. This study analyzed 134 endoscopic bile duct biopsy specimens (adenocarcinoma 45, atypical 31, and benign 58) by immunohistochemistry for the expression of maspin, a serine protease inhibitor. The results demonstrated that (1) maspin expression was more frequently detected in malignant than in benign biopsies; (2) malignant biopsies frequently showed diffuse, strong/intermediate, and combined nuclear/cytoplasmic staining patterns for maspin, which were much less commonly seen in benign biopsies; (3) the malignant staining patterns for maspin observed in atypical biopsies were consistent with follow-up data showing that 67% of these patients were subsequently diagnosed with adenocarcinoma; (4) a maspin+/S100P+/pVHL- staining profile was seen in 75% of malignant biopsies but in none of the benign cases. These observations demonstrate that maspin is a useful addition to the diagnostic immunohistochemical panel (S100P, pVHL, and insulin-like growth factor II mRNA-binding protein 3) to help distinguish malignant from benign epithelia on challenging bile duct biopsies.

Hsu YL, Hung JY, Liang YY, et al.
S100P interacts with integrin α7 and increases cancer cell migration and invasion in lung cancer.
Oncotarget. 2015; 6(30):29585-98 [PubMed] Free Access to Full Article Related Publications
S100P, a Ca2+ binding protein, has been shown to be overexpressed in various cancers. However, its functional character in lung cancer remains largely unknown. In this study, we show that S100P increases cancer migration, invasion and metastasis in lung cancer cells. Ectopic expression of S100P increases migration, invasion and EMT in less invasive CL1-0 lung cancer cells. Conversely, knockdown of S100P suppressed migration and invasion, and caused a reversion of EMT in highly invasive lung cancer cells. These effects were transduced by increasing the interaction of S100P with integrin α7, which activated focal adhesion kinase (FAK) and AKT. Blocking FAK significantly decreased S100P-induced migration by decreasing Src and AKT activation, whereas inhibiting AKT reduced S100P upregulation on ZEB1 expression. Further study has indicated that S100P knockdown prevents the spread of highly metastatic human lung cancer in animal models. This study therefore suggests that S100P represents a critical activator of lung cancer metastasis. Detection and targeted treatment of S100P-expressing cancer is an attractive therapeutic strategy in treating lung cancer.

Mercado-Pimentel ME, Onyeagucha BC, Li Q, et al.
The S100P/RAGE signaling pathway regulates expression of microRNA-21 in colon cancer cells.
FEBS Lett. 2015; 589(18):2388-93 [PubMed] Free Access to Full Article Related Publications
S100P signaling through the receptor for advanced glycation end-products (RAGE) contributes to colon cancer invasion and metastasis, but the mechanistic features of this process are obscure. Here, we investigate whether activation of S100P/RAGE signaling regulates oncogenic microRNA-21 (miR-21). We show that exogenous S100P up-regulates miR-21 levels in human colon cancer cells, whereas knockdown of S100P results in a decrease of miR-21. Furthermore, blockage of RAGE with anti-RAGE antibody suppresses S100P induction of miR-21. In addition, we found that S100P induction of miR-21 expression involves ERK and is suppressed by the MEK inhibitor U0126. Also, S100P treatment stimulates the enrichment of c-Fos, and AP-1 family members, at the miR-21 gene promoter.

Wang Q, Zhang JG, Wang W
Expression and significance of S100P, CD147, and OCT4 in different prostate cancer tissue TNM stages.
Genet Mol Res. 2015; 14(2):6844-51 [PubMed] Related Publications
The aim of this project was to investigate the expression and significance of S100P, CD147, and OCT4 in prostate cancer tissue at different TNM stages. We enrolled 54 patients with prostate cancer, 40 with benign prostatic hyperplasia, and 20 subjects with normal prostates. S100P, CD147, and OCT4 were detected by immunohistochemistry. The positive rate of S100P detection was 18.52% in prostate cancer tissues, significantly lower than in normal and benign prostate hyperplasia tissues (P ˂ 0.05). The positive expression rate of CD147 and OCT4 were 100 and 77.38% in prostate cancer tissue, respectively, both markedly higher than in normal and benign prostate hyperplasia tissue (P ˂ 0.05). The positive rate of S100P in stage V was 0, which was significantly lower than in stages I (37.50%) and II (35.71%) (P ˂ 0.05). OCT4 expression in stages III (86.67%) and V (94.12%) was higher than in stage I (37.50%). The positive rate of S100P in patients with distant metastasis was 4%, which was significantly lower than that in patients without metastases (P ˂ 0.05). In contrast, the positive rate of OCT4 in patients with distant metastasis was 92%. S100P, CD147, and OCT4 expression in prostate cancer patients with different degrees of differentiation had no significant difference (P > 0.05). Overall, our results demonstrated that S100P expression in prostate cancer tissue was significantly decreased, whereas CD147 and OCT4 expression was increased. Their expression levels were closely associated with TNM stage and distant metastasis, but were not related to the degree of differentiation.

Maierthaler M, Kriegsmann M, Peng C, et al.
S100P and HYAL2 as prognostic markers for patients with triple-negative breast cancer.
Exp Mol Pathol. 2015; 99(1):180-7 [PubMed] Related Publications
Triple-negative breast cancer (TNBC) is a group of very aggressive breast tumours, characterised by lack of expression of oestrogen receptor (ER), progesterone receptor (PR) and erb-b2 receptor tyrosine kinase 2 (ERBB2/HER2). Nevertheless, TNBCs show different clinical characteristics and are very diverse regarding prognostic outcome. So far, only a few prognostic markers for TNBC have been reported that could be helpful for therapeutic stratification. Here we have analysed the expression of S100P and HYAL2 using immunohistochemistry (IHC) in a TNBC cohort of 98 patients with a follow-up for recurrence and death. TNBC patients with high expression of both proteins showed significantly shorter progression-free survival (PFS) (mean PFS=35.9months, P=0.001) compared to TNBC patients with high expression levels of only one of the proteins (mean PFS=69.4months) and to TNBC patients with low expression of both proteins (mean PFS=83.3months). Moreover, multivariate Cox-regression model showed the combined expression of S100P and HYAL2 as independent prognostic factor for PFS (P=0.001). The expression of S100P and HYAL2 indicated similar prognostic effect to the overall survival (OS) of TNBC patients. In addition, high expression levels of both S100P and HYAL2 showed significant association with different clinicopathological characteristics, such as more recurrence events (P=0.004), and higher occurrence of metastasis (P=0.002). Our study proposes S100P and HYAL2 as potential prognostic markers for TNBC.

Chien MH, Lee WJ, Hsieh FK, et al.
Keap1-Nrf2 Interaction Suppresses Cell Motility in Lung Adenocarcinomas by Targeting the S100P Protein.
Clin Cancer Res. 2015; 21(20):4719-32 [PubMed] Related Publications
PURPOSE: Kelch-like ECH-associated protein 1 (Keap1) is an E3 ligase participated in the cellular defense response against oxidative stress through nuclear factor erythroid-2-related factor 2 (Nrf2). However, the role of Keap1 in regulating cancer motility is still controversial. We investigated the contribution of the Keap1-Nrf2 axis in the progression of non-small cell lung cancer (NSCLC).
EXPERIMENTAL DESIGN: The expression of Keap1 and Nrf2 was examined via immunohistochemistry, real-time PCR, and Western blot analysis in a cohort of NSCLC tissues and cells. A series of in vivo and in vitro assays was performed to elucidate the contribution of the Keap1-Nrf2 axis in lung cancer mobility and progression.
RESULTS: Keap1 expression was decreased in specimens from NSCLC patients with lymph node metastasis compared with patients without metastasis. Higher Keap1 expression levels were correlated with the survival of NSCLC patients. Moreover, manipulation of Keap1 expression affected cell migration/invasion abilities. Depletion of Nrf2 relieved the migration promotion imposed by Keap1 suppression. Mechanistic investigations found that S100P was downregulated in both Keap1-overexpressing and Nrf2-knockdown NSCLC cells. Overexpression of Keap1 and knockdown of Nrf2 both suppressed S100P expression in NSCLC cells. Knockdown of S100P inhibited cell migration in highly invasive NSCLC cells and also relieved the migration promotion imposed by Keap1 suppression in weakly invasive NSCLC cells.
CONCLUSIONS: Our findings suggest that Keap1 functions as a suppressor of tumor metastasis by targeting the Nrf2/S100P pathway in NSCLC cells. In addition, overexpression of Keap1 may be a novel NSCLC treatment strategy and/or useful biomarker for predicting NSCLC progression.

Martin JL, Gottehrer N, Zalesin H, et al.
Evaluation of Salivary Transcriptome Markers for the Early Detection of Oral Squamous Cell Cancer in a Prospective Blinded Trial.
Compend Contin Educ Dent. 2015; 36(5):365-73 [PubMed] Related Publications
BACKGROUND: Oral squamous cell cancer (OSCC) is often diagnosed in late stages. Informative biomarkers could play a key role in early diagnosis. Prior case-control studies identified discriminatory salivary mRNA markers for OSCC. The National Cancer Institute (NCI) recommends prospective-specimencollection, retrospective-blinded-evaluation (PRoBE) design study for rigorous biomarker identification and validation.
METHODS: A PRoBE design study enrolled 170 patients with lesions suspicious for OSCC. Saliva was collected before performing oral biopsy. Six pre-specified oral-cancer-associated mRNAs (IL1β, IL8, OAZ1, SAT, S100P, and DUSP1) and five housekeeping mRNAs (MT-ATP6, RPL30, RPL37A, RPL0, and RPS17) were measured by quantitative polymerase chain reaction (PCR) without knowledge of tissue diagnosis. A pre-specified multi-marker panel from prior NCI - Early Detection Research Network (EDRN) studies was evaluated in this new PRoBE dataset. Individual marker cycle thresholds (Ct) from PCR were also compared in cancer versus control, and new discriminatory models were generated.
RESULTS: The EDRN model was validated based on pre-specified statistical analysis plan. Ct values of individual mRNAs reflect an approximately twofold to nearly fourfold increase in concentration in invasive OSCC (P less than 0.01 for all). A new model from this intended-use population with incorporation of housekeeping genes demonstrates a maximal sum of sensitivity and specificity of 150.7% with an area under the receiver operating characteristic (ROC) curve of over 0.85.
CONCLUSION: The validation of six pre-specified individual salivary transcriptome markers of OSCC and a pre-specified multi-marker model in a new prospective population supports the robustness of these markers and the multi-marker methodology. New models generated in this intended-use population have the potential to further enhance the decision process for early biopsy. Lesions at very low risk for cancer could be identified noninvasively as could those at significantly increased risk. Further study is necessary to assure effective implementation of this technology into routine clinical practice.

Sávio AL, da Silva GN, Salvadori DM
Inhibition of bladder cancer cell proliferation by allyl isothiocyanate (mustard essential oil).
Mutat Res. 2015; 771:29-35 [PubMed] Related Publications
Natural compounds hold great promise for combating antibiotic resistance, the failure to control some diseases, the emergence of new diseases and the toxicity of some contemporary medical products. Allyl isothiocyanate (AITC), which is abundant in cruciferous vegetables and mustard seeds and is commonly referred to as mustard essential oil, exhibits promising antineoplastic activity against bladder cancer, although its mechanism of action is not fully understood. Therefore, the aim of this study was to investigate the effects of AITC activity on bladder cancer cell lines carrying a wild type (wt; RT4) or mutated (T24) TP53 gene. Morphological changes, cell cycle kinetics and CDK1, SMAD4, BAX, BCL2, ANLN and S100P gene expression were evaluated. In both cell lines, treatment with AITC inhibited cell proliferation (at 62.5, 72.5, 82.5 and 92.5μM AITC) and induced morphological changes, including scattered and elongated cells and cellular debris. Gene expression profiles revealed increased S100P and BAX and decreased BCL2 expression in RT4 cells following AITC treatment. T24 cells displayed increased BCL2, BAX and ANLN and decreased S100P expression. No changes in SMAD4 and CDK1 expression were observed in either cell line. In conclusion, AITC inhibits cell proliferation independent of TP53 status. However, the mechanism of action of AITC differed in the two cell lines; in RT4 cells, it mainly acted via the classical BAX/BCL2 pathway, while in T24 cells, AITC modulated the activities of ANLN (related to cytokinesis) and S100P. These data confirm the role of AITC as a potential antiproliferative compound that modulates gene expression according to the tumor cell TP53 genotype.

Chiang JM, Tan R, Wang JY, et al.
S100P, a calcium-binding protein, is preferentially associated with the growth of polypoid tumors in colorectal cancer.
Int J Mol Med. 2015; 35(3):675-83 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is a genetically heterogeneous disease with distinct morphological patterns. It has been shown that polypoid and ulcerative CRC displays different genetic alterations. In the present study, we aimed to investigate genes with differential expression patterns between ulcerative and polypoid CRC. cDNA microarray analysis was performed to compare the gene expression profiles in samples of ulcerative and polypoid CRC with paired normal mucosa samples. Potential candidate genes were further validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot analysis and immunohistochemistry. The epigenetic regulation of gene expression was investigated using methylation-specific PCR (MSP). cDNA microarray analysis identified 11 upregulated and 14 downregulated genes which were differentially expressed in samples from both tumor types compared to the matched normal mucosa samples. Among these, S100P was the only upregulated gene preferentially associated with polypoid CRC (P=0.032). The samples of polypoid CRC displayed significantly higher S100P protein and mRNA expression levels than the samples of ulcerative CRC (P<0.05, respectively). Using semi-quantitative immunohistochemical analyses, S100P overexpression was found to be preferentially associated with polypoid CRC (24/30 vs. 14/40, P<0.001). The relative methylation level determined by MSP did not differ significantly between the samples of polypoid and ulcerative CRC (43.36 vs. 49.10%, P=0.168), indicating that promoter hypomethylation was not directly related to the upregulation of S100P mRNA. Our results demonstrate that the upregulation of S100P mRNA and protein expression is a predominant characteristic in polypoid CRC, whereas ulcerative CRC presents with a wide range of expression levels, indicating that S100P overexpression is not a key determinant in conferring invasion properties. The clinicopathological significance of S100P in CRC requires further investigation in well-controlled studies.

Terai H, Soejima K, Yasuda H, et al.
Long‑term exposure to gefitinib induces acquired resistance through DNA methylation changes in the EGFR‑mutant PC9 lung cancer cell line.
Int J Oncol. 2015; 46(1):430-6 [PubMed] Related Publications
This study was designed to identify epigenetically regulated genes and to clarify the contribution of epige-netic alteration to acquired resistance to epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs). We established a gefitinib‑resistant lung cancer cell line, PC9, which was originally gefitinib‑sensitive, by serial long‑term exposure to gefitinib. RNA and DNA were collected from both gefitinib‑sensitive and ‑resistant PC9 cells, and comprehensive DNA methylation and mRNA expression analyses were performed using Infinium HumanMethylation27 Bead Arrays and Agilent SurePrint G3 Human Gene Expression 8x60K Array, respectively. DNA methylation was increased in 640 genes in gefitinib‑resistant cells compared to parental cells. Among them, we selected 29 candidate genes that presented a decrease in mRNA expression in resistant PC9. We further studied four of the selected genes (C10orf116, IGFBP3, KL, and S100P) and found that KL or S100P silencing by siRNA induced a decrease in gefitinib sensitivity compared to that in the negative control in PC9. In conclusion, KL and S100P could be potential targets to overcome resistance to EGFR‑TKIs.

Zhang Q, Zhu M, Cheng W, et al.
Downregulation of 425G>a variant of calcium-binding protein S100A14 associated with poor differentiation and prognosis in gastric cancer.
J Cancer Res Clin Oncol. 2015; 141(4):691-703 [PubMed] Related Publications
PURPOSE: Altered level of S100 calcium-binding proteins is involved in tumor development and progression. However, their role in gastric cancer (GC) is not well documented. We investigated the expression pattern of S100 proteins and differentiation or prognosis as well as possible mechanisms in GC.
METHODS: RT-PCR, Western blot analysis, and immunohistochemistry were used to determine the mRNA and protein expression of S100 family genes in GC. The polymorphisms of promoter and 5'-UTR of S100A14 gene were identified and related to luciferase reporter gene activity. Association of S100A14 expression with clinicopathologic features and survival in GC was analyzed.
RESULTS: We detected upregulated S100A2, S100A6, S100A10, and S100A11 expression and downregulated S100P and S100B expression in GC. Particularly, we detected differential mRNA and protein expression of S100A14 in GC cell lines and primary tumors. Furthermore, S100A14 expression change was related to a differentiated GC phenotype, with an expression in 31/40 (77.5 %) samples of well-differentiated tumors and 29/85 (34.1 %) samples of poorly differentiated tumors (P < 0.001). Moreover, 5-year survival was better in GC cases with positive than negative S100A14 level (P = 0.02). The genetic variant 425G>A on the 5'-UTR of S100A14 was associated with reduced S100A14 expression in GC cells.
CONCLUSION: Decreased expression of S100A14 with presence of its genetic variant 425G>A may be associated with an undifferentiated phenotype and poor prognosis in GC.

Xie H, Lee L, Scicluna P, et al.
Novel functions and targets of miR-944 in human cervical cancer cells.
Int J Cancer. 2015; 136(5):E230-41 [PubMed] Free Access to Full Article Related Publications
Altered expression of specific microRNAs (miRNAs) has been observed in human cervical cancer. However, the biological functions of many of these miRNAs are yet to be discovered. We previously showed that miR-944 is significantly more abundant in cervical cancer tissues than their normal counterparts. In this study, we investigated the functions and targets of miR-944 in human cervical cancer cells. MiR-944 is located in the intron of the tumor protein p63 (TP63) gene, which is frequently overexpressed in cervical carcinomas. Using gain- and loss-of-function experiments in vitro, we demonstrate that miR-944 promotes cell proliferation, migration and invasion, but has no effect on apoptosis, in human cervical cancer cells. To identify the targets of miR-944, we performed photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation followed by deep sequencing. Among the candidate targets, we validated HECW2 (HECT domain ligase W2) and S100PBP (S100P binding protein) as direct targets of miR-944 using luciferase reporter assays and western blot analysis. Our findings reveal novel functions and targets of miR-944 in human cervical cancer cells, which may provide new insights of its role in cervical carcinogenesis.

Guo L, Chen S, Jiang H, et al.
The expression of S100P increases and promotes cellular proliferation by increasing nuclear translocation of β-catenin in endometrial cancer.
Int J Clin Exp Pathol. 2014; 7(5):2102-12 [PubMed] Free Access to Full Article Related Publications
There is increasing evidence suggesting that S100P has a significant role in cancer, and is associated with poor clinical outcomes. The expression of S100P mRNA and protein in endometrial cancer and normal endometrium tissues was detected by real-time quantitative RT-PCR and immunohistochemistry. Moreover, we reduced the expression of S100P in HEC-1A and Ishikawa endometrial cancer cell lines by siRNA transfection. Based on the reduced S100P mRNA expression, we measured the effects of S100P on cellular proliferation by the cell-counting kit-8. Nuclear β-catenin protein level was detected by western blotting. Cyclin D1 and c-myc mRNA expression regulated by β-catenin was detected by real-time quantitative RT-PCR. We found that the expression of S100P mRNA and protein increased in endometrial cancer tissues compared with the normal endometrium. Local S100P expression progressively increased from pathologic differenciation grade 1 to 3. After reducing the S100P expression, the cellular proliferation ability, nuclear β-catenin protein level, cyclin D1 and c-myc mRNA levels reduced. It indicated that S100P could promote cell proliferation by increasing nuclear translocation of β-catenin. The expression of S100P mRNA and protein in endometrial cancer significantly increased and is associated with pathologic differenciation grade. S100P may promote endometrial cell proliferation by increasing nuclear translocation of β-catenin.

Sims JN, Graham B, Pacurari M, et al.
Di-ethylhexylphthalate (DEHP) modulates cell invasion, migration and anchorage independent growth through targeting S100P in LN-229 glioblastoma cells.
Int J Environ Res Public Health. 2014; 11(5):5006-19 [PubMed] Free Access to Full Article Related Publications
Glioblastoma multiforme (GBM) is the most aggressive brain cancer with a median survival of 1-2 years. The treatment of GBM includes surgical resection, radiation and chemotherapy, which minimally extends survival. This poor prognosis necessitates the identification of novel molecular targets associated with glioblastoma. S100P is associated with drug resistance, metastasis, and poor clinical outcomes in many malignancies. The functional role of S100P in glioblastoma has not been fully investigated. In this study, we examined the role of S100P mediating the effects of the environmental contaminant, DEHP, in glioblastoma cells (LN-229) by assessing cell proliferation, apoptosis, anchorage independent growth, cell migration and invasion following DEHP exposure. Silencing S100P and DEHP treatment inhibited LN-229 glioblastoma cell proliferation and induced apoptosis. Anchorage independent growth study revealed significantly decreased colony formation in shS100P cells. We also observed reduced cell migration in cells treated with DEHP following S100P knockdown. Similar results were observed in spheroid formation and expansion. This study is the first to demonstrate the effects of DEHP on glioblastoma cells, and implicates S100P as a potential therapeutic target that may be useful as a drug response biomarker.

Jiang Y, Liu M, Li Z, Jiang Y
Discovery of novel candidate oncogenes in pancreatic carcinoma using high-throughput microarrays.
Hepatogastroenterology. 2013 Nov-Dec; 60(128):1825-32 [PubMed] Related Publications
BACKGROUND/AIMS: Pancreatic cancer is one of the most aggressive tumors in mankind. Its aggressiveness is only due to the biological progressive characteristics but also the difficulty for clinical early detection which urges us to find diagnostic tools for early diagnosis. Biomarkers are a developing tool used to measure molecules such as proteins, DNA, or RNAs in blood samples or suspected tumor tissues. The molecular dysregulation is believed to play major roles in tumorigenesis or a result after the tumor formation and can be used as a biomarker for tumor detection.
METHODOLOGY: In this paper, we studied the gene expression profiles using tissues from pancreatic cancer patients.
RESULTS: We observed dysregulation of gene expression profiles using high-throughput sequencing technique and verified three-gene upregulation, REG4, CDH3 and S100P both in pancreatic cell lines and carcinoma tissues by RT-PCR and Northern Blot. A detailed description of the genes involved is listed within this article.
CONCLUSIONS: We believe that by unraveling the gene dysregulation profiles in pancreatic tumor tissues can we achieve an early and precise diagnosis of pancreatic cancer. Moreover, these newly found genes, due to their functions involved in cell migration and mitosis, may play major roles in tumorigensis.

Zhang YW, Zheng Y, Wang JZ, et al.
Integrated analysis of DNA methylation and mRNA expression profiling reveals candidate genes associated with cisplatin resistance in non-small cell lung cancer.
Epigenetics. 2014; 9(6):896-909 [PubMed] Free Access to Full Article Related Publications
DNA methylation plays a critical role during the development of acquired chemoresistance. The aim of this study was to identify candidate DNA methylation drivers of cisplatin (DDP) resistance in non-small cell lung cancer (NSCLC). The A549/DDP cell line was established by continuous exposure of A549 cells to increasing concentrations of DDP. Gene expression and methylation profiling were determined by high-throughput microarrays. Relationship of methylation status and DDP response was validated in primary tumor cell culture and the Cancer Genome Atlas (TCGA) samples. Cell proliferation, apoptosis, cell cycle, and response to DDP were determined in vitro and in vivo. A total of 372 genes showed hypermethylation and downregulation in A549/DDP cells, and these genes were involved in most fundamental biological processes. Ten candidate genes (S100P, GDA, WISP2, LOXL1, TIMP4, ICAM1, CLMP, HSP8, GAS1, BMP2) were selected, and exhibited varying degrees of association with DDP resistance. Low dose combination of 5-aza-2'-deoxycytidine (5-Aza-dC) and trichostatin A (TSA) reversed drug resistance of A549/DDP cells in vitro and in vivo, along with demethylation and restoration of expression of candidate genes (GAS1, TIMP4, ICAM1 and WISP2). Forced expression of GAS1 in A549/DDP cells by gene transfection contributed to increased sensitivity to DDP, proliferation inhibition, cell cycle arrest, apoptosis enhancement, and in vivo growth retardation. Together, our study demonstrated that a panel of candidate genes downregulated by DNA methylation induced DDP resistance in NSCLC, and showed that epigenetic therapy resensitized cells to DDP.

Wu TS, Tan CT, Chang CC, et al.
B-cell lymphoma/leukemia 10 promotes oral cancer progression through STAT1/ATF4/S100P signaling pathway.
Oncogene. 2015; 34(10):1207-19 [PubMed] Related Publications
B-cell lymphoma/leukemia 10 (BCL10) is an apoptotic regulatory protein related to advanced TNM stage and disease recurrence in oral squamous cell carcinoma (OSCC). However, the regulatory mechanism of BCL10 in OSCC progression is still unknown. Here, we showed that knockdown of endogenous BCL10 could significantly reduce cell migration and invasion abilities, retard cell proliferation by G0/G1 phase accumulation and inhibit tumorigenicity in vivo. In molecular level, we identified S100P as a crucial downstream effector of BCL10-inhibited OSCC progression by high-throughput microarray analysis. S100P messenger RNA and protein expression levels were significantly diminished in silenced-BCL10 clones, and transfected S100P expression plasmids restored migration, invasion, proliferation abilities and tumorigenicity in shBCL10 transfectants. Furthermore, we provided evidence that BCL10 regulated S100P expression through signal transducers and activators of transcription 1 (STAT1) and activating transcription factor 4 (ATF4). Knockdown of BCL10 decreased S100P promoter activity, but showed no effect in truncated STAT1/ATF4 S100P promoter.  In addition, we also found that the P50/P65 signaling pathway was involved in BCL10-enhanced OSCC progression. Restored S100P in silenced-BCL10 clones could markedly reverse P65 activation via outside-in signaling. Taken together, we discovered a novel axis of BCL10-regulated OSCC progression via STAT1/ATF4/S100P/P65 signaling, which could predict the prognosis of OSCC and will be beneficial for developing therapeutic strategy against advanced OSCC.

Zhang Q, Hu H, Shi X, Tang W
Knockdown of S100P by lentiviral-mediated RNAi promotes apoptosis and suppresses the colony-formation ability of gastric cancer cells.
Oncol Rep. 2014; 31(5):2344-50 [PubMed] Related Publications
S100P is a putative candidate oncogene in several types of human tumors. However, expression of S100P, its potential role and its clinical significance in gastric cancer remain unclear. In the present study, S100P expression was examined by immunohistochemistry using a tissue microarray. Positive staining for S100P was noted in 77.1% of the cases while 22.9% were negative. In two gastric cancer cell lines, MGC-803 and SGC-7901, S100P expression was knocked down by a lentiviral short hairpin delivery system. The RNA interference-mediated downregulation of S100P expression markedly promoted cell apoptosis and inhibited cell colony-formation ability of the gastric cancer cells. In addition, knockdown of S100P significantly regulated the expression of 12 apoptosis-associated genes with a >1.5-fold change compared with the negative control. Among them, FOS, DDIT3 and FN1 were significantly upregulated, while FASLG, DAPK1, CTNNB1 and CASP2 were notably downregulated following S100P silencing. These results suggest that S100P acts as an oncogenic factor in gastric cancer and is a potential molecular target for gastric cancer gene therapy.

Wang L, Wang Y, Guo C
Editing genomic DNA in cancer cells with high genetic variance: benefit or risk?
Oncol Rep. 2014; 31(5):2079-84 [PubMed] Related Publications
The generation of stably-transfected cell lines is a common and very important technology in cancer science. Considerable knowledge in the field of life sciences has been gained through the modification of the genetic code. However, there is a risk in evaluating exogenous gene function through editing genomic DNA in a cancer cell with high genetic variance. In the present study, we showed that genomic DNA status should be considered when evaluating the exogenous gene function in a cancer cell line with high variant genome through stable transfection technology, immunostaining, wound healing assay, transwell invasion assay, real-time PCR, western blot and karyotyping analysis. Our results showed that the S100P expression level was not related to the migration and invasion abilities in these stably transfected cell lines derived from a human salivary adenoid cystic carcinoma cell line SACC-83. The MMP expression pattern was detected by western blot analysis which matched the biological behaviors in these cells. The genomic analysis showed that SACC-83 presented hypotetraploid karyotyping with high variance. Our data indicated that establishment of stable transgenic cancer cell lines should consider the status of genetic variance in a cancer cell to avoid any biased conclusion.

Nakanuma Y, Sato Y
Hilar cholangiocarcinoma is pathologically similar to pancreatic duct adenocarcinoma: suggestions of similar background and development.
J Hepatobiliary Pancreat Sci. 2014; 21(7):441-7 [PubMed] Related Publications
Routine experiences suggest that cholangiocarcinomas (CCAs) show different clinicopathological behaviors along the biliary tree, and hilar CCA apparently resembles pancreatic duct adenocarcinoma (PDAC). Herein, the backgrounds for these similarities were reviewed. While all cases of PDAC, hilar CCA, intrahepatic CCA (ICCA) and CCA components of combined hepatocellular-cholangiocarcinoma (cHC-CCA) were adenocarcinomas, micropapillary patterns and columnar carcinoma cells were common in PDAC and hilar CCA, and trabecular components and cuboidal carcinoma cells were common in ICCA and CCA components of cHC-CCA. Anterior gradient protein-2 and S100P were frequently expressed in perihilar CCA and PDAC, while neural cell adhesion molecule and luminal epithelial membrane antigen were common in CCA components of c-HC-CCA. Pdx1 and Hes1 were frequently and markedly expressed aberrantly in PDAC and perihilar CCA, although their expression was rare and mild in CCA components in cHC-CCA and ICCA. Hilar CCA showed a similar postoperative prognosis to PDAC but differed from ICCA and cHC-CCA. Taken together, hilar CCA may differ from ICCA and CCA components of cHC-CCA but have a similar development to PDAC. These similarities may be explained by the unique anatomical, embryological and reactive nature of the pancreatobiliary tract. Further studies of these intractable malignancies are warranted.

Hamada S, Masamune A, Miura S, et al.
MiR-365 induces gemcitabine resistance in pancreatic cancer cells by targeting the adaptor protein SHC1 and pro-apoptotic regulator BAX.
Cell Signal. 2014; 26(2):179-85 [PubMed] Related Publications
The poor prognosis of invasive ductal adenocarcinoma of the pancreas is mainly due to its resistance against therapeutic agents. The molecular mechanism by which morbidity enhances cell survival has been extensively studied, but radical improvements in the therapeutic strategy have not yet been achieved. Recent reports have indicated the substantial contribution of miRNA in multiple cell functions by comprehensively targeting clusters of genes. We identified several miRNAs highly expressed in invasive ductal adenocarcinoma in our previous study, and clarified their contribution to the epithelial-mesenchymal transition. Among the differentially expressed miRNAs, miR-365 was highly expressed in invasive ductal adenocarcinoma, whose functional role has not been reported. In the current study, we found that miR-365 induced gemcitabine resistance in pancreatic cancer cells. MiR-365 directly targeted adaptor protein Src Homology 2 Domain Containing 1 (SHC1) and apoptosis-promoting protein BAX. The siRNA-based knockdown of SHC1 and BAX increased gemcitabine resistance, indicating the miR-365/SHC1/BAX axis influences the survival of pancreatic cancer cells. In addition, miR-365 up-regulated cancer-promoting molecules such as Inhibitor of DNA binding 2 and S100P, suggesting the existence of cross-talk with other cancer-promoting signals. MiR-365 could exert orchestrated effects on pancreatic cancer cell survival.

Mo ML, Okamoto J, Chen Z, et al.
Down-regulation of SIX3 is associated with clinical outcome in lung adenocarcinoma.
PLoS One. 2013; 8(8):e71816 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lung cancer is a common cancer and the leading cause of cancer-related death worldwide. SIX3 is a human homologue of the highly conserved sine oculis gene family essential during embryonic development in vertebrates, and encodes a homeo-domain containing transcription factor. Little is known about the role of SIX3 in human tumorigenesis. This study is to assess the expression/function of SIX3 and the significance of SIX3 as a prognostic biomarker in lung adenocarcinoma.
METHODS: Quantitative real-time RT-PCR was used to analyze SIX3 mRNA expression and quantitative methylation specific PCR (MSP) was used to examine promoter methylation. MTS and colony formation assays were performed to examine cell proliferation. Wound healing assays were used to assess cell migration, and microarrays were utilized to examine genes regulated by SIX3 in lung cancer cells. Association of SIX3 expression levels with clinical outcomes of patients with lung adenocarcinoma was evaluated using the Kaplan-Meier method and a multivariate Cox proportional hazards regression model.
RESULTS: SIX3 was down-regulated in lung adenocarcinoma tissues compared to their matched adjacent normal tissues, and this down-regulation was associated with methylation of the SIX3 promoter. SIX3 was also methylation-silenced in lung cancer cell lines. Restoration of SIX3 in lung cancer cells lacking endogenous SIX3 suppressed cell proliferation and migration, and downregulated a number of genes involved in proliferation and metastasis such as S100P, TGFB3, GINS3 and BAG1. Moreover, SIX3 mRNA expression was associated with significantly improved overall survival (OS) and progression-free survival (PFS) in adenocarcinoma patients and patients with bronchioloalveolar carcinoma (BAC) features.
CONCLUSIONS: SIX3 may play an important role as a novel suppressor in human lung cancer. SIX3 has potential as a novel prognostic biomarker for patients with lung adenocarcinomas.

Cheng YS, Jordan L, Rees T, et al.
Levels of potential oral cancer salivary mRNA biomarkers in oral cancer patients in remission and oral lichen planus patients.
Clin Oral Investig. 2014; 18(3):985-93 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: To gather preliminary data concerning the feasibility of using seven salivary mRNAs-IL-8; IL-1β; dual specificity phosphatase 1 (DUSP1); H3 histone family 3A (H3F3A); ornithin decarboxylase antizyme 1 (OAZ1); S100 calcium-binding protein P (S100P); and spermidine/spermine N1-acetyltransferase 1 (SAT1)-for detecting development of oral squamous cell carcinoma (OSCC) in oral lichen planus (OLP) patients and OSCC patients whose disease was in remission.
MATERIALS AND METHODS: Saliva samples were collected from five study groups (25 subjects/group): newly diagnosed OSCC, OSCC-in-remission, disease-active OLP, disease-inactive OLP, and normal controls. The salivary mRNA levels were determined by a pre-amplification RT-qPCR approach with nested gene-specific primers. Mean fold changes between each pair of study groups were analyzed by the Mann-Whitney U test.
RESULTS: Salivary levels of OAZ1, S100P, and DUSP1 mRNAs were significantly higher in newly diagnosed OSCC patients, compared to: (1) normal controls (p = 0.003; p = 0.003; and p < 0.001, respectively); (2) OSCC-in-remission (p < 0.001; p = 0.001; and p < 0.001, respectively); (3) disease-active OLP (p < 0.001; p = 0.016; and p < 0.001, respectively); and (4) disease-inactive OLP (p = 0.043; p < 0.001; and p < 0.001, respectively). No significant differences were found in the levels of salivary IL-8, IL-1β, H3F3A, and SAT1 mRNAs between newly diagnosed OSCC patients and the normal controls (p = 0.093, 0.327, 0.764, and 0.560, respectively).
CONCLUSION: Salivary OAZ1, S100P, and DUSP1 mRNAs are candidate biomarkers for detecting OSCC development in OSCC patients in remission and in OLP patients.
CLINICAL RELEVANCE: The results of this study serve as the basis for a further large-scale study which may lead to a non-invasive screening method for early detection of OSCC.

Yuan RH, Chang KT, Chen YL, et al.
S100P expression is a novel prognostic factor in hepatocellular carcinoma and predicts survival in patients with high tumor stage or early recurrent tumors.
PLoS One. 2013; 8(6):e65501 [PubMed] Free Access to Full Article Related Publications
The calcium-binding protein S100P is expressed in a variety of human cancer cells and is important in cancer cell growth and invasion. Using differential display, we found S100P is overexpressed in human hepatocellular carcinoma (HCC). We examined the expression of 305 unifocal, primary HCC tumors using immunohistochemistry. The S100P protein was expressed in 173 of the 305 (56.7%) HCC tumors. The expression of S100P correlated with female sex (P = 0.0162), high serum α-fetoprotein level (P = 0.0001), high tumor grade (P = 0.0029), high tumor stage (P = 0.0319), the presence of the p53 mutation (P = 0.0032), and the absence of the β-catenin mutation (P = 0.0489). Patients with HCC tumors that expressed S100P were more likely to have early tumor recurrence (ETR) (P = 0.0189) and lower 5-year survival (P = 0.0023). The multivariate analysis confirmed that S100P expression was an independent prognostic factor in HCC. The combinatorial analysis showed an additive unfavorable prognostic interaction between S100P expression and the p53 mutation. In contrast, the β-catenin mutation was associated with better prognosis in both S100P-positive and -negative HCCs. Furthermore, S100P expression was a predictor of survival in HCC patients with high tumor stage or ETR (P = 0.0026 and P = 0.0002, respectively). Our study indicates the expression of the S100P protein is a novel independent predictor for poor prognosis in HCC, and it is also an unfavorable prognostic predictor in HCC patients with high tumor stage or ETR.

Ko CH, Cheng CF, Lai CP, et al.
Differential proteomic analysis of cancer stem cell properties in hepatocellular carcinomas by isobaric tag labeling and mass spectrometry.
J Proteome Res. 2013; 12(8):3573-85 [PubMed] Related Publications
Malignant tumors are relatively resistant to treatment due to their heterogeneous nature, drug resistance, and tendency for metastasis. Recent studies suggest that a subpopulation of cancer cells is responsible for the malignant outcomes. These cells are considered as cancer stem cells (CSC). Although a number of molecules have been identified in different cancer cells as markers for cancer stem cells, no promising markers are currently available for hepatocellular carcinoma cells. In this study, two clones of Hep3B cell lines were functionally characterized as control or CSC-like cells, based on properties including spheroid formation, drug resistance, and tumor initiation. Furthermore, their protein expression profiles were investigated by isobaric tags for relative and absolute quantitation (iTRAQ), and a total of 1,127 proteins were identified and quantified from the combined fractions; 50 proteins exhibited at least 2-fold differences between these two clones. These 50 proteins were analyzed by GeneGo and were found to be associated with liver neoplasms, hepatocellular carcinoma (HCC), and liver diseases. They were also components of metabolic pathways, immune responses, and cytoskeleton remodeling. Among these proteins, the expressions of S100P, S100A14, and vimentin were verified in several HCC cell lines, and their expressions were correlated with tumorigenicity in HCC cell lines. The functional significance of vimentin and S100A14 were also investigated and verified.

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