S100A4; S100 calcium binding protein A4 (1q21)

Gene Summary

Gene:S100A4; S100 calcium binding protein A4
Aliases: 42A, 18A2, CAPL, FSP1, MTS1, P9KA, PEL98
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. This protein may function in motility, invasion, and tubulin polymerization. Chromosomal rearrangements and altered expression of this gene have been implicated in tumor metastasis. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protein S100-A4
Updated:14 December, 2014


What does this gene/protein do?
Show (10)

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (9)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Colorectal CancerS100A4 and Colorectal Cancer View Publications57
Breast CancerS100A4 and Breast Cancer View Publications31
OsteosarcomaS100A4 expression in OsteosarcomaPrognostic View Publications18
Pancreatic CancerS100A4 and Pancreatic Cancer View Publications17
Colorectal CancerS100A4 and Colorectal Cancer View Publications17
Lung CancerS100A4 and Lung Cancer View Publications14
Stomach CancerS100A4 and Stomach Cancer View Publications10
Skin CancerS100A4 and Skin Cancer View Publications3

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: S100A4 (cancer-related)

Oliveira MV, Fraga CA, Barros LO, et al.
High expression of S100A4 and endoglin is associated with metastatic disease in head and neck squamous cell carcinoma.
Clin Exp Metastasis. 2014; 31(6):639-49 [PubMed] Related Publications
The presence of cervical metastasis is responsible for high morbidity and mortality rates in individuals with head and neck squamous cell carcinoma (HNSCC). S100A4, a pleiotropic EF-hand calcium-binding protein, is expressed in various normal and cancer cell types. During cancer progression, molecular disturbances in S100A4 can modulate the activity and expression of pre-metastatic and metastatic genes. In this study, we investigated the association between S100A4 methylation status and protein expression as well as the expression of the S100A4 related-proteins annexin A2 (ANXA2), matrix metallopeptidase-9, and endoglin, for metastasis and other clinicopathological parameters in HNSCC. Formalin-fixed, paraffin-embedded blocks of metastatic and non-metastatic HNSCC and matched cervical lymph node (LN) samples (metastatic LN = mLN, non-metastatic = nmLN, and control LN (lymphadenitis) = cLN) were submitted for methylation specific-polymerase chain reaction and immunohistochemistry. Our results showed that S100A4 methylation status failed to demonstrate association with cervical metastasis and other clinicopathological factors related to HNSCC. HNSCC samples from patients that presented with metastatic disease showed high S100A4 and endoglin expression (p < 0.05). In conclusion, molecular disturbances in S100A4 and endoglin expression might regulate the formation of cervical metastasis in HNSCC.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology Angiogenesis and Cancer

Chen N, Sato D, Saiki Y, et al.
S100A4 is frequently overexpressed in lung cancer cells and promotes cell growth and cell motility.
Biochem Biophys Res Commun. 2014; 447(3):459-64 [PubMed] Related Publications
S100A4, a small calcium-binding protein belonging to the S100 protein family, is commonly overexpressed in a variety of tumor types and is widely accepted to associate with metastasis by regulating the motility and invasiveness of cancer cells. However, its biological role in lung carcinogenesis is largely unknown. In this study, we found that S100A4 was frequently overexpressed in lung cancer cells, irrespective of histological subtype. Then we performed knockdown and forced expression of S100A4 in lung cancer cell lines and found that specific knockdown of S100A4 effectively suppressed cell proliferation only in lung cancer cells with S100A4-overexpression; forced expression of S100A4 accelerated cell motility only in S100A4 low-expressing lung cancer cells. PRDM2 and VASH1, identified as novel upregulated genes by microarray after specific knockdown of S100A4 in pancreatic cancer, were also analyzed, and we found that PRDM2 was significantly upregulated after S100A4-knockdown in one of two analyzed S100A4-overexpressing lung cancer cells. Our present results suggest that S100A4 plays an important role in lung carcinogenesis by means of cell proliferation and motility by a pathway similar to that in pancreatic cancer.

Related: Lung Cancer PRDM2

Nutter F, Holen I, Brown HK, et al.
Different molecular profiles are associated with breast cancer cell homing compared with colonisation of bone: evidence using a novel bone-seeking cell line.
Endocr Relat Cancer. 2014; 21(2):327-41 [PubMed] Related Publications
Advanced breast cancer is associated with the development of incurable bone metastasis. The two key processes involved, tumour cell homing to and subsequent colonisation of bone, remain to be clearly defined. Genetic studies have indicated that different genes facilitate homing and colonisation of secondary sites. To identify specific changes in gene and protein expression associated with bone-homing or colonisation, we have developed a novel bone-seeking clone of MDA-MB-231 breast cancer cells that exclusively forms tumours in long bones following i.v. injection in nude mice. Bone-homing cells were indistinguishable from parental cells in terms of growth rate in vitro and when grown subcutaneously in vivo. Only bone-homing ability differed between the lines; once established in bone, tumours from both lines displayed similar rates of progression and caused the same extent of lytic bone disease. By comparing the molecular profile of a panel of metastasis-associated genes, we have identified differential expression profiles associated with bone-homing or colonisation. Bone-homing cells had decreased expression of the cell adhesion molecule fibronectin and the migration and calcium signal binding protein S100A4, in addition to increased expression of interleukin 1B. Bone colonisation was associated with increased fibronectin and upregulation of molecules influencing signal transduction pathways and breakdown of extracellular matrix, including hRAS and matrix metalloproteinase 9. Our data support the hypothesis that during early stages of breast cancer bone metastasis, a specific set of genes are altered to facilitate bone-homing, and that disruption of these may be required for effective therapeutic targeting of this process.

Related: Breast Cancer

Walter I, Wolfesberger B, Miller I, et al.
Human osteosarcoma cells respond to sorafenib chemotherapy by downregulation of the tumor progression factors S100A4, CXCR4 and the oncogene FOS.
Oncol Rep. 2014; 31(3):1147-56 [PubMed] Related Publications
Osteosarcoma is a rare but aggressive bone neoplasm in humans, which is commonly treated with surgery, classical chemotherapy and radiation. Sorafenib, an inhibitor of a number of kinases targeting the Raf/MEK/ERK pathway, is a promising new chemotherapeutic agent in human medicine that has been approved since 2006 for the therapy of renal cell carcinoma and since 2007 for the treatment of hepatocellular carcinoma. Here, we studied the antimetastatic potential of 4 µM of this multikinase inhibitor in a human osteosarcoma cell line. DNA microarray-based gene expression profiling detected 297 and 232 genes upregulated or downregulated at a threshold of >2-fold expression alteration (P<0.05) in the sorafenib-treated cells. Three genes (CXCR4, FOS and S100A4) that are involved in tumor progression were chosen for validation by quantitative PCR (qPCR) and protein expression analysis. The decrease in RNA expression detected by microarray profiling was confirmed by qPCR for all three genes (P<0.01). On the protein level, sorafenib-induced reduction of S100A4 was verified both by western blotting and immunohistochemistry. For CXCR4 and c-Fos, a reduced protein expression was shown by immunohistochemistry, for c-Fos also by immunoblotting. We conclude that sorafenib could serve as a potent chemotherapeutical agent by which to inhibit the metastatic progression of osteosarcomas.

Related: Bone Cancers Secondary Bone Cancer (bone metastasis) Osteosarcoma Sorafenib (Nexavar)

Asraf H, Salomon S, Nevo A, et al.
The ZnR/GPR39 interacts with the CaSR to enhance signaling in prostate and salivary epithelia.
J Cell Physiol. 2014; 229(7):868-77 [PubMed] Related Publications
Zinc signaling is mediated by the zinc sensing receptor, ZnR, recently suggested to be the same receptor as G-protein coupled receptor 39, GPR39. However, it is unknown if GPR39 is mediating Zn(2+) -dependent signaling in prostate and salivary tissue where changes in zinc concentrations are frequent and of physiological significance. Here, we show that GPR39 is mediating Zn(2+) -dependent Ca(2+) responses and is regulating activity of MAP and PI3 pathways in prostate cancer cells, PC3, and ductal salivary gland cells, HSY. We next ask whether ZnR/GPR39 interacts with other GPCR family members. We find that endogenous ZnR/GPR39 activity is regulated by the expression and activity of another cation sensing GPCR, the Ca(2+) -sensing receptor (CaSR). Although CaSR is not activated by Zn(2+), co-expression of CaSR and ZnR/GPR39 synergistically enhances Ca(2+) responses in PC3 and HSY cells. Silencing of the CaSR using siRNA or a dominant negative construct reduces the Zn(2+) -dependent signaling. Importantly, overexpression of GPR39 in HEK293 cells is sufficient to trigger Zn(2+) -dependent responses. Nevertheless, application of the CaSR agonist spermine, at concentration below its threshold, enhanced Zn(2+) -dependent Ca(2+) response. Our results suggest that the CaSR interacts with ZnR/GPR39 and thereby regulates its activity. Finally, we show that in PC3 cells ZnR/GPR39 is required for mediating the Zn(2+) -dependent activation of MAPK and PI3K, pathways leading to enhanced cell growth. Importantly, Zn(2+) -dependent activation of ZnR/GPR39 also enhances the expression of the Ca(2+) -binding protein S100A4 that is linked to invasion of prostate cancer cells.

Related: Prostate Cancer Signal Transduction

Rosenberg EE, Prudnikova TY, Zabarovsky ER, et al.
D-glucuronyl C5-epimerase cell type specifically affects angiogenesis pathway in different prostate cancer cells.
Tumour Biol. 2014; 35(4):3237-45 [PubMed] Related Publications
D-glucuronyl C5-epimerase (GLCE) is involved in breast and lung carcinogenesis as a potential tumor suppressor gene, acting through inhibition of tumor angiogenesis and invasion/metastasis pathways. However, in prostate tumors, increased GLCE expression is associated with advanced disease, suggesting versatile effects of GLCE in different cancers. To investigate further the potential cancer-promoting effect of GLCE in prostate cancer, GLCE was ectopically re-expressed in morphologically different LNCaP and PC3 prostate cancer cells. Transcriptional profiles of normal PNT2 prostate cells, LNCaP, PC3 and DU145 prostate cancer cells, and GLCE-expressing LNCaP and PC3 cells were determined. Comparative analysis revealed the genes whose expression was changed in prostate cancer cells compared with normal PNT2 cells, and those differently expressed between the cancer cell lines (ACTA2, IL6, SERPINE1, TAGLN, SEMA3A, and CDH2). GLCE re-expression influenced mainly angiogenesis-involved genes (ANGPT1, SERPINE1, IGF1, PDGFB, TNF, IL8, TEK, IFNA1, and IFNB1) but in a cell type-specific manner (from basic deregulation of angiogenesis in LNCaP cells to significant activation in PC3 cells). Invasion/metastasis pathway was also affected (MMP1, MMP2, MMP9, S100A4, ITGA1, ITGB3, ERBB2, and FAS). The obtained results suggest activation of angiogenesis as a main molecular mechanism of pro-oncogenic effect of GLCE in prostate cancer. GLCE up-regulation plus expression pattern of a panel of six genes, discriminating morphologically different prostate cancer cell sub-types, is suggested as a potential marker of aggressive prostate cancer.

Related: Angiogenesis and Cancer Prostate Cancer

Liang J, Piao Y, Holmes L, et al.
Neutrophils promote the malignant glioma phenotype through S100A4.
Clin Cancer Res. 2014; 20(1):187-98 [PubMed] Related Publications
PURPOSE: Antiangiogenic therapy is effective in blocking vascular permeability, inhibiting vascular proliferation, and slowing tumor growth, but studies in multiple cancer types have shown that tumors eventually acquire resistance to blockade of blood vessel growth. Currently, the mechanisms by which this resistance occurs are not well understood.
EXPERIMENTAL DESIGN: In this study, we evaluated the effects of neutrophils on glioma biology both in vitro and in vivo and determined target genes by which neutrophils promote the malignant glioma phenotype during anti-VEGF therapy.
RESULTS: We found that an increase in neutrophil infiltration into tumors is significantly correlated with glioma grade and in glioblastoma with acquired resistance to anti-VEGF therapy. Our data demonstrate that neutrophils and their condition media increased the proliferation rate of glioblastoma-initiating cells (GIC). In addition, neutrophils significantly increased GICs Transwell migration compared with controls. Consistent with this behavior, coculture with neutrophils promoted GICs to adopt morphologic and gene expression changes consistent with a mesenchymal signature. Neutrophil-promoting tumor progression could be blocked by S100A4 downregulation in vitro and in vivo. Furthermore, S100A4 depletion increased the effectiveness of anti-VEGF therapy in glioma.
CONCLUSIONS: Collectively, these data suggest that increased recruitment of neutrophils during anti-VEGF therapy promotes glioma progression and may promote treatment resistance. Tumor progression with mesenchymal characteristics is partly mediated by S100A4, the expression of which is increased by neutrophil infiltration. Targeting granulocytes and S100A4 may be effective approaches to inhibit the glioma malignant phenotype and diminish antiangiogenic therapy resistance.

Related: Angiogenesis Inhibitors VEGFA Bevacizumab (Avastin)

Rud AK, Boye K, Oijordsbakken M, et al.
Osteopontin is a prognostic biomarker in non-small cell lung cancer.
BMC Cancer. 2013; 13:540 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In a previously published report we characterized the expression of the metastasis-associated proteins S100A4, osteopontin (OPN) and ephrin-A1 in a prospectively collected panel of non-small cell lung cancer (NSCLC) tumors. The aim of the present follow-up study was to investigate the prognostic impact of these potential biomarkers in the same patient cohort. In addition, circulating serum levels of OPN were measured and single nucleotide polymorphisms (SNP) in the -443 position of the OPN promoter were analyzed.
METHODS: Associations between immunohistochemical expression of S100A4, OPN and ephrin-A1 and relapse free and overall survival were examined using univariate and multivariate analyses. Serum OPN was measured by ELISA, polymorphisms in the -443 position of the tumor OPN promoter were analyzed by PCR, and associations between OPN levels and promoter polymorphisms and clinicopathological parameters and patient outcome were investigated.
RESULTS: High expression of OPN in NSCLC tumors was associated with poor patient outcome, and OPN was a strong, independent prognostic factor for both relapse free and overall survival. Serum OPN levels increased according to tumor pT classification and tumor size, and patients with OPN-expressing tumors had higher serum levels than patients with OPN-negative tumors. S100A4 was a negative prognostic factor in several subgroups of adenocarcinoma patients, but not in the overall patient cohort. There was no association between ephrin-A1 expression and patient outcome.
CONCLUSIONS: OPN is a promising prognostic biomarker in NSCLC, and should be further explored in the selection of patients for adjuvant treatment following surgical resection.

Related: Non-Small Cell Lung Cancer Lung Cancer

Liu J, Xu ZM, Qiu GB, et al.
S100A4 is upregulated via the binding of c-Myb in methylation-free laryngeal cancer cells.
Oncol Rep. 2014; 31(1):442-9 [PubMed] Related Publications
DNA hypomethylation is correlated with the overexpression of the S100A4 gene in several types of cancers including laryngeal cancer, but the molecular mechanism is unknown. We speculated that the methylation status of the promoter affects its binding to the corresponding transcription factors. In the present study, luciferase reporter assay results indicated that the sequences -485 - +73 and -486 - -530 of the S100A4 promoter may harbor the positive and negative cis-acting elements, respectively; and moreover, the luciferase activity promoted by the sequence -485 - +73 increased and the S100A4 gene was significantly upregulated in 5-Aza-induced HEp2 cells. This implies that the methylation status of the sequence is important in regulating the expression of S100A4. Four transcription factor binding motifs including c-Myb, C/EBpα, Ap2 and Msx-1 in the region were predicted by P-Match software. c-Myb and C/EBpα but not Ap2 and Msx-1 were confirmed by EMSA and ChIP as transcription factors of S100A4. The decreased luciferase activity in methylation-free HEp2 cells transfected by the mutant c-Myb motif related to the methylated cytosine suggests that the hypomethylation of the c-Myb motif upregulates the S100A4 expression in laryngeal cancer.

Related: Cancer of the Larynx Laryngeal Cancer - Molecular Biology

Zhang J, Zhang DL, Jiao XL, Dong Q
S100A4 regulates migration and invasion in hepatocellular carcinoma HepG2 cells via NF-κB-dependent MMP-9 signal.
Eur Rev Med Pharmacol Sci. 2013; 17(17):2372-82 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: We previously showed that the calcium-binding protein S100A4 is overexpressed and related to metastasis in hepatocellular carcinoma (HCC). However, whether S100A4 participates in the regulation of metastasis and its mechanisms in HCC is mostly unknown. Given the associations of S100A4, nuclear factor-kB (NF-kB/RelA) and MMP-9 with metastasis in a variety of malignancies, we explored a potential role of S100A4 in HCC metastasis and its mechanism.
METHODS: 20 patients with HCC invasion (Lymph node metastasis, microvascular invasion, major portal vein invasion and intrahepatic metastasis) and 20 patients without HCC invasion were included. These tissues were detected for the expression of S100A4, NF-kB/RelA and MMP-9 by immunohistochemistry and quantitative real time polymerase chain reaction (Q-PCR). Correlation between the expressions of S100A4, NF-kB/RelA and MMP-9 with the invasion was analysed. The expressions of S100A4, nuclear factor-kB and MMP-9 was evaluated in HepG2 cells by western blot and immunohistochemistry. HepG2 cells were stably transfected with S100A4-specific small interfering RNA (S100A4 siRNA) to knockdown of S100A4, then transiently transfected with S100A4 cDNA to rescure the S100A4 level and evaluated for effects on invasion and expression analysis for molecules involved in invasion. After the HepG2 cells recurred the S100A4 levels, the HepG2 cells was treated with 5 µM Pyrrolidine Dithiocarbamate (PDTC) (a selective NF κ B inhibitor) to inhibit the NF-kB activity, or treated with Batimast (BB94: a MMPs inhibitor) to inhibit the MMP-9 activity. The expression analysis for molecules involved in invasion was analyzed.
RESULTS: A significant increase of S100A4, NF-kB/RelA and MMP-9 expression in HCC tissues with invasion than that of without invasion. A positive correlation was observed between S100A4, NF-kB/RelA, MMP-9 and invasion, respectively. In addition, S100A4 was positively correlated with NF-kB and MMP-9. S100A4 siRNA mediated knockdown of S100A4 in HepG2 cells resulted in significant reduction in the NF-kB activity and MMP-9 expression, and dramatically decreased its invasion. Moreover, the HepG2 cell metastatic potential was rescued by overexpression of S100A4 completely, at the same time, the NF-kB activity and MMP-9 expression was also increased. Pretreatment with PDTC or BB94 was observed to significantly reduce NF-kB activity and MMP-9 expression and dramatically decreased S100A4 -induced invasion.
CONCLUSIONS: Our findings indicate that S100A4 contributes to HCC metastasis by activation of NF-kB dependent MMP-9 expression, suggesting S100A4 as a novel diagnostic biomarker and therapeutic target in HCC.

Related: Liver Cancer MMP9: matrix metallopeptidase 9

Nouraee N, Van Roosbroeck K, Vasei M, et al.
Expression, tissue distribution and function of miR-21 in esophageal squamous cell carcinoma.
PLoS One. 2013; 8(9):e73009 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: MiR-21 is an oncomir expressed by malignant cells and/or tumor microenvironment components. In this study we focused on understanding the effects of stromal miR-21 on esophageal malignant cells.
DESIGN: MiR-21 expression was evaluated in formalin-fixed paraffin-embedded samples from patients with esophageal squamous-cell carcinoma (SCC) by quantitative RT-PCR. MiR-21 tissue distribution was visualized with in situ hybridization. A co-culture system of normal fibroblasts and esophageal cancer cells was used to determine the effects of fibroblasts on miR-21 expression levels, and on SCC cell migration and invasion.
RESULTS: MiR-21 was overexpressed in SCCs, when compared to the adjacent non-tumor tissues (P = 0.0007), and was mainly localized in the cytoplasm of stromal cells adjacent to malignant cells. Accordingly, miR-21 expression was increased in tumors with high versus low stromal content (P = 0.04). When co-cultured with normal fibroblasts, miR-21 expression was elevated in SCC cells (KYSE-30), while its expression was restricted to fibroblasts when co-cultured with adenocarcinoma cells (OE-33 and FLO-1). MiR-21 was detected in conditioned media of cancer cell lines, illustrating the release of this miRNA into the environment. Co-culturing with normal fibroblasts or addition of fibroblast conditioned media caused a significant increase in cell migration and invasion potency of KYSE-30 cells (P<0.0001). In addition, co-culturing cancer cells with fibroblasts and expression of miR-21 induced the expression of the cancer associated fibroblast (CAF) marker S100A4.
CONCLUSIONS: MiR-21 expression is mostly confined to the SCC stroma and its release from fibroblasts influences the migration and invasion capacity of SCC cells. Moreover, miR-21 may be an important factor in "activating" fibroblasts to CAFs. These findings provide new insights into the role of CAFs and the extracellular matrix in tumor microenvironment formation and in tumor cell maintenance, and suggest miR-21 may contribute to cellular crosstalk in the tumor microenvironment.

Related: Cancer of the Esophagus Esophageal Cancer miR-21

Rasanen K, Sriswasdi S, Valiga A, et al.
Comparative secretome analysis of epithelial and mesenchymal subpopulations of head and neck squamous cell carcinoma identifies S100A4 as a potential therapeutic target.
Mol Cell Proteomics. 2013; 12(12):3778-92 [PubMed] Free Access to Full Article Related Publications
Epithelial-mesenchymal transition (EMT) is a key contributor in tumor progression and metastasis. EMT produces cellular heterogeneity within head and neck squamous cell carcinomas (HNSCC) by creating a phenotypically distinct mesenchymal subpopulation that is resistant to conventional therapies. In this study, we systematically characterized differences in the secretomes of E-cadherin high epithelial-like and E-cadherin low mesenchymal-like subpopulations using unbiased and targeted proteomics. A total 1765 proteins showed significant changes with 177 elevated in the epithelial subpopulation and 173 elevated in the mesenchymal cells. Key nodes in affected networks included NFκB, Akt, and ERK, and most implicated cellular components involved various aspects of the extracellular matrix. In particular, large changes were observed in multiple collagens with most affected collagens at much higher abundance levels in the mesenchymal subpopulation. These cells also exhibited a secretome profile resembling that of cancer-associated fibroblastic cells (CAF). S100A4, a commonly used marker for cancer-associated fibroblastic cells, was elevated more than 20-fold in the mesenchymal cells and this increase was further verified at the transcriptome level. S100A4 is a known mediator of EMT, leading to metastasis and EMT has been proposed as a potential source of cancer-associated fibroblastic cells in solid tumors. S100A4 knockdown by small interfering RNA led to decreased expression, secretion and activity of matrix metalloproteinase 2, as verified by quantitative PCR, multiple reaction monitoring and zymography analyses, and reduced invasion in collagen-embedded spheroids. Further confirmation in three-dimensional organotypic reconstructs showed less invasion and advanced differentiation in the S100A4 RNA interference samples. Orthotopic metastasis model, developed to validate the findings in vivo, demonstrated a decrease in spontaneous metastasis and augmented differentiation in the primary tumor in siS100A4 xenografts. These results demonstrate the value of secretome profiling to evaluate phenotypic conversion and identify potential novel therapeutic targets such as S100A4.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology MMP2 AKT1 Signal Transduction

Biniossek ML, Lechel A, Rudolph KL, et al.
Quantitative proteomic profiling of tumor cell response to telomere dysfunction using isotope-coded protein labeling (ICPL) reveals interaction network of candidate senescence markers.
J Proteomics. 2013; 91:515-35 [PubMed] Related Publications
UNLABELLED: Telomerase inhibition causes progressive telomere shortening and cellular senescence, which constitutes a universal barrier to tumor growth and therefore an attractive target for tumor therapy. To expand our previous studies, we investigated the global effects of telomere dysfunction on the proteome of tumor cells in order to find novel senescence biomarkers. Telomerase-deficient HCT-116 cell clones were analyzed by a quantitative proteomic approach using isotope-coded protein labeling (ICPL) and nanoflow-HPLC-MS/MS. Stringent reduction of the extensive proteomic data from this tumor cell model revealed a list of 59 markers including proteins identified in our former studies and a number of novel proteins involved in tumorigenesis and metastasis such as SFN, S100A4, ANXA2, and LGALS1. A loss of the chromatin protein HMGB2 was demonstrated not only in various telomerase-inhibited clones of different tumor cell lines, but also in normal human fibroblasts undergoing replicative senescence and in aging telomerase knockout mice. Impressively, a coherent and dense network of protein-protein interactions for the bulk of the markers and their implementation in signaling pathways involving key regulators for tumorigenesis were revealed. These results have an impact on the understanding of telomere- and senescence-related signal transduction in tumor cells in consideration of the general lack of senescence markers.
BIOLOGICAL SIGNIFICANCE: Induction of cellular senescence constitutes a potent concept for tumor therapy which interferes with immortalization and additional hallmarks of cancer. The application of a powerful quantitative proteomic approach using isotope-coded protein labeling to an approved model for senescence represented by telomerase inhibited tumor cells led to the identification of novel candidate biomarkers for telomere dysfunction and replicative senescence. Thereby, the identified markers not only fit in the context of the investigated processes with a relevance for additional hallmarks of cancer but are also involved in a strong interaction network and integrated in canonical pathways centered around key cancer-relevant proteins. These potential markers alone or in combination will significantly extend the view on telomere-associated signal transduction in tumor cells and contribute to the field of cellular senescence and aging in consideration of the general lack of biomarkers in this regard.

Related: Mitochondrial Mutations in Cancer Signal Transduction

Ochiya T, Takenaga K, Endo H
Silencing of S100A4, a metastasis-associated protein, in endothelial cells inhibits tumor angiogenesis and growth.
Angiogenesis. 2014; 17(1):17-26 [PubMed] Free Access to Full Article Related Publications
Endothelial cells express S100A4, a metastasis-associated protein, but its role in angiogenesis remains to be elucidated. Here we show that knockdown of S100A4 in mouse endothelial MSS31 cells by murine specific small interference RNA (mS100A4 siRNA) markedly suppressed capillary-like tube formation in vitro, in early stage after the treatment, along with down- and up-regulation of some of the pro-angiogenic and anti-angiogenic gene expression, respectively. Of particular note is that intra-tumor administration of the mS100A4 siRNA in a human prostate cancer xenograft significantly reduced tumor vascularity and resulted in the inhibition of tumor growth. These findings show that S100A4 in endothelial cells is involved in tube formation, and suggest its potential as a molecular target for inhibiting tumor angiogenesis, which warrants further development of endothelial S100A4-based strategies for cancer treatment.

Related: Angiogenesis and Cancer Prostate Cancer

Kozono S, Ohuchida K, Ohtsuka T, et al.
S100A4 mRNA expression level is a predictor of radioresistance of pancreatic cancer cells.
Oncol Rep. 2013; 30(4):1601-8 [PubMed] Related Publications
Improving poor outcomes in patients with pancreatic cancer requires a greater understanding of the biological mechanisms contributing to radioresistance. We, therefore, sought to identify genes involved in the radioresistance of pancreatic cancer cells. Two pancreatic cancer cell lines, CFPAC-1 and Capan-1, were repeatedly exposed to radiation, establishing two radioresistant cell lines. Gene expression profiling using cDNA microarrays was performed to identify genes responsible for radioresistance. The levels of expression of mRNAs encoded by selected genes and their correlation with radiation dose resulting in 50% survival rate were analyzed in pancreatic cancer cell lines. The radiation dose resulting in a 50% survival rate was significantly higher in irradiated (IR) compared to parental CFPAC-1 cells (8.31 ± 0.85 Gy vs. 2.14 ± 0.04 Gy, P<0.0001), but was lower in IR compared with parental Capan-1 cells (2.66 ± 0.24 Gy vs. 2.25 ± 0.03 Gy, P=0.04). cDNA microarray analysis identified 4 genes, including S100 calcium binding protein A4 (S100A4), overexpressed and 23 genes underexpressed in the IR compared with the parental cell lines. The levels of S100A4 mRNA expression were correlated with radiation dose resulting in a 50% survival rate (Pearson's test, R2=0.81, P=0.0025). S100A4 mRNA expression may predict radioresistance of pancreatic cancer cells and may play an important role in the poor response of pancreatic cancer cells to radiation therapy.

Related: Cancer of the Pancreas Pancreatic Cancer

Zhang H, Liu J, Yue D, et al.
Clinical significance of E-cadherin, β-catenin, vimentin and S100A4 expression in completely resected squamous cell lung carcinoma.
J Clin Pathol. 2013; 66(11):937-45 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to evaluate the prognostic value of E-cadherin, β-catenin, vimentin and S100A4 expression in a cohort of squamous cell lung carcinoma (SqCC) patients.
METHODS: Tumours from 204 patients with surgically resected SqCC were used for the immunohistochemical analyses of E-cadherin, β-catenin, vimentin and S100A4 expression. Correlations between the expression of these markers and clinicopathological parameters were analysed using the χ(2) test. The prognostic value of these markers was evaluated using univariate Kaplan-Meier survival analyses and multivariate Cox proportional hazards model analyses.
RESULTS: Significant associations between E-cadherin expression and T stage (p=0.040), histological differentiation (p=0.005), lymph node metastasis (p<0.001), and recurrence (p<0.001) were identified. Decreased β-catenin expression was significantly correlated with T stage (p=0.003) and lymph node metastasis (p=0.010). Vimentin expression was associated with histological differentiation (p=0.017) and lymph node metastasis (p=0.001). Moreover, significant correlations were observed between S100A4 expression and lymph node metastasis (p=0.020) and recurrence (p<0.001). In the univariate analyses, high E-cadherin expression was a positive indicator for overall survival (OS) (p<0.001) and disease-free survival (DFS) (p<0.001), whereas high S100A4 or vimentin expression were negative indicators for OS (p<0.001 and p=0.010, respectively) and DFS (p<0.001 and p=0.006, respectively). In the multivariate analyses, E-cadherin and S100A4 expression were independent prognostic factors for OS (HR 0.697, 95% CI 0.524 to 0.926, p=0.013, and HR 1.508, 95% CI 1.122 to 2.027, p=0.007, respectively) and DFS (HR 0.634, 95% CI 0.471 to 0.852, p=0.003, and HR 1.490, 95% CI 1.101 to 2.015, p=0.010, respectively).
CONCLUSIONS: Effective analysis of E-cadherin and S100A4 expression may allow for the identification of patients who are at a high risk of recurrence and poor prognosis in SqCC.

Related: Lung Cancer CTNNB1 gene

Yang XC, Wang X, Luo L, et al.
RNA interference suppression of A100A4 reduces the growth and metastatic phenotype of human renal cancer cells via NF-kB-dependent MMP-2 and bcl-2 pathway.
Eur Rev Med Pharmacol Sci. 2013; 17(12):1669-80 [PubMed] Related Publications
BACKGROUND AND AIM: S100A4 is a well established marker and mediator of metastatic disease, but the exact mechanisms responsible for the metastasis promoting effects are less well defined. We tested a hypothesis that the S100A4 gene plays a role in the proliferation and invasiveness of human renal cancer cells (RCC) and may be associated with its metastatic spread.
MATERIALS AND METHODS: The small interference RNA vector pcDNA3.1-S100A4 siRNA was transfected in to the human renal cancer cell lines ACHN, Ketr-3, OS-RC-2, CaKi-2 and HTB-47, then treated with ABT-737 or BB94. Cell apoptosis and cell viability was detected by flow cytometry and MTT assay. Matrigel was used for cell motility and invasion assay. MMP-2, bcl-2 and S100A4 was detected by RT-PCR and western blot assay. NF-kB subunit p65 activity was detected by confocal microscopy assay. We then determine the effect S100A4 sliencing on tumor growth, lung metastasis development in vivo. Immunohistochemistry was used to detected the expression of S100A4, bcl-2, MMP-2, p65 and CD31.
RESULTS: S100A4 silencing in ACHN cells by RNA interference significantly inhibited NF-kB and NF-kB-mediated MMP-2 and bcl-2 activation and cellular migration, proliferation, and promoted apoptosis. Furthermore, re-expression of S100A4 in S100A4-siRNA-transfected ACHN cells by transient S100A4 cDNA transfection restored the NF-kB and NF-kB-mediated MMP-2 and bcl-2 activation and their high migratory and cellular proliferative ability. An inhibitor ABT-737 (the Bcl-2 antagonist targets Bcl-2) against Bcl-2 suppressed cellular proliferation and promoted apoptosis induced by S100A4 re-expression in S100A4-siRNA-transfected ACHN cells. A inhibitor BB94 against MMPs to neutralize MMP-2 protein suppressed cellular invasion and migration induced by S100A4 re-expression in S100A4-siRNA-transfected ACHN cells. In the prevention model, S100A4 silencing inhibited primary tumor growth by (tumor weight) (76 ± 8%) and (tumor volum) (78 ± 4%) respectively and promoted apoptosis and the formation of lung metastases was inhibited by 89% (p < 0.01). Microvascular density was reduced by 70% (p < 0.01). In addition, S100A4 sliencing inhibited the expression of S100A4 in vivo, followed by the NF-kB, MMP-2 and bcl-2 suppression.
CONCLUSIONS: We conclude that S100A4 plays a crucial role in proliferation and migratory/invasive processes in human RCC by a mechanism involving activation of NF-kB-bcl-2 and NF-kB-MMP-2 pathway.

Related: Kidney Cancer MMP2

Li Y, Hu J, Huang H, He Y
Effect of Jinlong capsule on proliferation and apoptosis of human pancreatic cancer cells BxPC-3.
J Tradit Chin Med. 2013; 33(2):205-10 [PubMed] Related Publications
OBJECTIVE: To study the possible roles of Jinlong capsule (JLC) on the proliferation and apoptosis of human pancreatic cancer cells BxPC-3.
METHODS: The human pancreatic cancer cells BxPC-3 were treated with JLC at the concentration of 0.05-1.00 mg/mL for 24-120 h. The inhibition rate of JLC on human pancreatic cancer cells BxPC-3 was detected by 3-(4,5-dimethiylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. Flow cytometry was employed to measure cell apoptosis using Annexin V-FITC/Propidium iodide (AV-FITC/PI) method. Cell cycles were determined by PI staining. The expression of 5100 Calcium binding protein A4 (S100A4) in cell matrix was measured by enzyme-linked immunosorbent assay (ELISA). The expression levels of apoptosis-related protein such as BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), B-cell lymphoma/leukemia-2 (Bcl-2) and Cys-teinylaspartate specific proteinase 3 (Caspase-3) were detected by Western blotting.
RESULTS: JLC significantly inhibited the proliferation of human pancreatic cancer cells BxPC-3 in a dose-dependent and time-dependent manner. JLC promoted cell apoptosis and maintained cell cycle in S and G2/M phase rather than G1/G0 phase. The expression of 5100A4 in the cell matrix was reduced. The expression of cell apoptotic protein BNIP3 was increased while Bcl-2 was decreased.
CONCLUSION: JLC can inhibit the proliferation of human pancreatic cancer cells BxPC-3 by stimulating cell apoptosis, arresting the cell cycle at S and G2/M phase which blocks the circulation of normal cell cycle and reducing the expression of S100A4 protein. Higher pro-apoptosis protein BNIP3 and lower anti-apoptosis protein Bcl-2 levels were found, which may be related to the apoptotic effects of JLC.

Related: Apoptosis Cancer of the Pancreas Pancreatic Cancer

Liu Z, Liu H, Pan H, et al.
Clinicopathological significance of S100A4 expression in human hepatocellular carcinoma.
J Int Med Res. 2013; 41(2):457-62 [PubMed] Related Publications
OBJECTIVE: Prognostic markers for hepatocellular carcinoma (HCC) could help in the clinical management and understanding of its poor prognosis. S100 calcium binding protein A4 (S100A4) is directly involved in tumour metastasis. This study evaluated S100A4 gene expression in human HCC, to identify its role in tumour progression.
METHODS: In this retrospective study, S100A4 protein levels in HCC samples from Chinese patients were evaluated using immunohistochemistry and compared with paired normal tumour-adjacent tissue samples (controls). All patients were evaluated for HCC recurrence.
RESULTS: S100A4 levels were significantly increased in HCC samples compared with controls (n = 72, each sample type). Moderately or poorly differentiated tumours had significantly higher levels of S100A4 protein than well-differentiated tumours, and those with tumour vascular invasion showed significantly higher S100A4 levels than those without invasion. Risk of recurrence increased in patients positive for S100A4, and S100A4 positivity correlated with a shorter overall survival time.
CONCLUSION: This pilot study suggests S100A4 as a likely tumour marker for HCC that correlates with tumour differentiation, invasion, recurrence and overall survival. S100A4 could be a useful marker of tumour aggressiveness and prognosis.

Related: Liver Cancer Childhood Liver Cancer

Jia W, Gao XJ, Zhang ZD, et al.
S100A4 silencing suppresses proliferation, angiogenesis and invasion of thyroid cancer cells through downregulation of MMP-9 and VEGF.
Eur Rev Med Pharmacol Sci. 2013; 17(11):1495-508 [PubMed] Related Publications
BACKGROUND AND AIM: It is well documented that S100A4 is upregulated in many cancers and plays a pivotal role in tumor proliferation, invasion, metastasis and angiogenesis. However, the precise role and mechanism S100A4 exerts in the thyroid cancer have not been fully elucidated to date. In the present study, we investigated the effect of S100A4 on proliferation, invasion, metastasis and angiogenesis in thyroid cancer cells.
MATERIALS AND METHODS: A plasmid construct was made that expressed full long S100A4 cDNA. The construct was stably transfected into BCPAP and ML-1 thyroid cancer cells (BCPAP/ S100A4 cDNA, ML-1/S100A4 cDNA). S100A4 siRNA was transiently transfected into the DRO cells (DRO/S100A4 siRNA). MMP-9 siRNA or VEGF siRNA was transiently transfected into the BCPAP/ S100A4 cDNA, ML-1/S100A4 cDNA cells (BCPAP/ S100A4 cDNA/VEGF siRNA, ML-1/S100A4 cDNA/ MMP-9 siRNA).
RESULTS: We found that the down-regulation of S100A4 by small interfering RNA decreased cell invasion, metastasis, and angiogenesis by using chicken chorioallantoic membrane (CAM), whereas S100A4 overexpression by cDNA transfection led to increased tumor cell invasion, metastasis, and angiogenesis. Consistent with these results, we found that the down-regulation of S100A4 reduced VEGF and MMP-9 expression. Furthermore, Knockdown of MMP-9 by MMP-9 siRNA inhibited cell invasion and metastasis in the BCPAP/S100A4 cDNA, ML-1/S100A4 cDNA cells. Knockdown of VEGF by VEGF siRNA inhibited cell angiogenesis in the BCPAP/ S100A4 cDNA, ML-1/S100A4 cDNA cells.We also found that downregulation of S100A4 by small interfering RNA resulted in enhanced cell growth inhibition and apoptosis, and vice versa. Our data suggest S100A4 could be an effective approach for the regulation of proliferation, invasion and angiogenesis. Downregulation of S100A4 could inhibit angiogenesis, proliferation and invasion by regulating the expression of MMP-9 and VEGF.
CONCLUSIONS: Our results provide evidence that the downregulation of S100A4 using RNAi technology may provide an effective tool for thyroid cancer therapy.

Related: Apoptosis MMP9: matrix metallopeptidase 9 Angiogenesis and Cancer Thyroid Cancer VEGFA

Hu T, Zhang C, Tang Q, et al.
Variant G6PD levels promote tumor cell proliferation or apoptosis via the STAT3/5 pathway in the human melanoma xenograft mouse model.
BMC Cancer. 2013; 13:251 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD), elevated in tumor cells, catalyzes the first reaction in the pentose-phosphate pathway. The regulation mechanism of G6PD and pathological change in human melanoma growth remains unknown.
METHODS: HEM (human epidermal melanocyte) cells and human melanoma cells with the wild-type G6PD gene (A375-WT), G6PD deficiency (A375-G6PD∆), G6PD cDNA overexpression (A375-G6PD∆-G6PD-WT), and mutant G6PD cDNA (A375-G6PD∆-G6PD-G487A) were subcutaneously injected into 5 groups of nude mice. Expressions of G6PD, STAT3, STAT5, cell cycle-related proteins, and apoptotic proteins as well as mechanistic exploration of STAT3/STAT5 were determined by quantitative real-time PCR (qRT-PCR), immunohistochemistry and western blot.
RESULTS: Delayed formation and slowed growth were apparent in A375-G6PD∆ cells, compared to A375-WT cells. Significantly decreased G6PD expression and activity were observed in tumor tissues induced by A375-G6PD∆, along with down-regulated cell cycle proteins cyclin D1, cyclin E, p53, and S100A4. Apoptosis-inhibited factors Bcl-2 and Bcl-xl were up-regulated; however, apoptosis factor Fas was down-regulated, compared to A375-WT cells. Moderate protein expressions were observed in A375-G6PD∆-G6PD-WT and A375-G6PD∆-G6PD-G487A cells.
CONCLUSIONS: G6PD may regulate apoptosis and expression of cell cycle-related proteins through phosphorylation of transcription factors STAT3 and STAT5, thus mediating formation and growth of human melanoma cells. Further study will, however, be required to determine potential clinical applications.

Related: Apoptosis Melanoma Signal Transduction

Björk P, Källberg E, Wellmar U, et al.
Common interactions between S100A4 and S100A9 defined by a novel chemical probe.
PLoS One. 2013; 8(5):e63012 [PubMed] Free Access to Full Article Related Publications
S100A4 and S100A9 proteins have been described as playing roles in the control of tumor growth and metastasis. We show here that a chemical probe, oxyclozanide (OX), selected for inhibiting the interaction between S100A9 and the receptor for advanced glycation end-products (RAGE) interacts with both S100A9 and S100A4. Furthermore, we show that S100A9 and S100A4 interact with RAGE and TLR4; interactions that can be inhibited by OX. Hence, S100A4 and S100A9 display similar functional elements despite their primary sequence diversity. This was further confirmed by showing that S100A4 and S100A9 dimerize both in vitro and in vivo. All of these interactions required levels of Zn++ that are found in the extracellular space but not intracellularly. Interestingly, S100A4 and S100A9 are expressed by distinct CD11b+ subpopulations both in healthy animals and in animals with either inflammatory disease or tumor burden. The functions of S100A9 and S100A4 described in this paper, including heterodimerization, may therefore reflect S100A9 and S100A4 that are released into the extra-cellular milieu.

Related: S100A9

Min HS, Lee C, Jung KC
Correlation of immunohistochemical markers and BRAF mutation status with histological variants of papillary thyroid carcinoma in the Korean population.
J Korean Med Sci. 2013; 28(4):534-41 [PubMed] Free Access to Full Article Related Publications
Several pathologic characteristics are associated with an adverse clinical outcome in papillary thyroid carcinoma (PTC), including the histological variant. This study aimed to investigate immunohistochemical expression and BRAF mutation status based on the histological variant and evaluated potential markers of aggressive behavior of PTC in Korean patients. In all, 407 PTC cases were classified to each histological variant, and the 94 representative cases were subjected to immunohistochemistry and BRAF mutation analysis. The classic type, follicular variant (FV) and tall cell variant (TCV) represented 76.9%, 14.2% and 6%, respectively. TCV showed a larger tumor size (P = 0.009), frequent extrathyroidal extension (P = 0.022) and cervical lymph node (LN) metastasis (P = 0.018). TCV and FV showed the reduced expression of galectin-3 (P = 0.003) and HBME1 (P = 0.114). Regardless of histology, PTEN loss and diffuse S100A4 expression were associated with LN metastasis (P = 0.007, P = 0.013). All TCVs harbored BRAF V600E mutation, and FV harbored less BRAF V600E mutation (P = 0.043). Immunohistochemical evaluation showed characteristic patterns in histological variants. PTEN and S100A4 expression are suggested as indicators of regional lymph node metastasis.

Related: PTEN BRAF gene Thyroid Cancer

Chen D, Zhang R, Shen W, et al.
RPS12-specific shRNA inhibits the proliferation, migration of BGC823 gastric cancer cells with S100A4 as a downstream effector.
Int J Oncol. 2013; 42(5):1763-9 [PubMed] Related Publications
Our previous study using suppression subtractive hybridization (SSH), cDNA microarray and semi-quantitative RT-PCR showed that RPS12 was overexpressed in gastric cancer and it was closely related to metastasis. However, the role of RPS12 in gastric cancer is not clear, which led us to conduct the current study to further investigate the effects of RPS12 on the proliferation and migration of gastric cancer cells, and also to explore the underlying molecular mechanisms. RNA interference was used to inhibit the expression of RPS12. The expression of RPS12 and S100A4 in gastric cancer cells was determined using semi-quantitative RT-PCR and western blot analysis. Cell proliferation and migration were detected by MTT and transwell assay, respectively. In addition, the promoter activity of S100A4 was measured by a Dual-Luciferase Reporter Assay System. We found that RNAi‑mediated RPS12 downregulation led to reduced proliferation and migration of BGC823 and SGC7901 gastric cancer cells. Further results showed that RPS12 inhibition led to reduced S100A4 expression and decreased promoter activity of S100A4 in BGC823 cells. We demonstrated that ectopic expression of S100A4 reversed the reduced proliferation and migration ability after RPS12 inhibition in BGC823 cells. Our findings provide the first demonstration that RPS12 plays important roles in regulating the proliferation and migration of gastric cancer cells. S100A4 can mediate the effects of RPS12 as a downstream effector.

Related: Stomach Cancer Gastric Cancer

Stein U, Burock S, Herrmann P, et al.
Circulating MACC1 transcripts in colorectal cancer patient plasma predict metastasis and prognosis.
PLoS One. 2012; 7(11):e49249 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metastasis is the most frequent cause of treatment failure and death in colorectal cancer. Early detection of tumors and metastases is crucial for improving treatment strategies and patient outcome. Development of reliable biomarkers and simple tests routinely applicable in the clinic for detection, prognostication, and therapy monitoring is of special interest. We recently identified the novel gene Metastasis-Associated in Colon Cancer 1 (MACC1), a key regulator of the HGF/Met-pathway. MACC1 is a strong prognostic biomarker for colon cancer metastasis and allows identification of high-risk subjects in early stages, when determined in patients' primary tumors. To overcome the limitation of a restricted number of molecular analyses in tumor tissue, the establishment of a non-invasive blood test for early identification of high-risk cancer patients, for monitoring disease course and therapy response is strongly needed.
METHODOLOGY/PRINCIPAL FINDINGS: For the first time, we describe a non-invasive assay for quantification of circulating MACC1 transcripts in blood of more than 300 colorectal cancer patients. MACC1 transcript levels are increased in all disease stages of the cancer patients compared to tumor-free volunteers. Highest MACC1 levels were determined in individuals with metastases (all P<0.05). Importantly, high MACC1 levels correlate with unfavorable survival (P<.0001). Combining MACC1 with circulating transcripts of the metastasis gene S100A4, a transcriptional target of the Wnt/β-catenin-pathway, improves survival prediction for newly diagnosed cancer patients.
CONCLUSION/SIGNIFICANCE: This blood-based assay for circulating MACC1 transcripts, which can be quantitated on a routine basis, is clinically applicable for diagnosis, prognosis, and therapeutic monitoring of cancer patients. Here we demonstrate the diagnostic and prognostic value of circulating MACC1 transcripts in patient plasma for metastasis and survival. Since MACC1 represents a promising target for anti-metastatic therapies, circulating MACC1 transcripts may prove to be an ideal read-out for monitoring therapeutic response of future interventions targeting MACC1-induced metastasis in cancer patients.

Related: Colorectal (Bowel) Cancer

Wang L, Wang X, Liang Y, et al.
S100A4 promotes invasion and angiogenesis in breast cancer MDA-MB-231 cells by upregulating matrix metalloproteinase-13.
Acta Biochim Pol. 2012; 59(4):593-8 [PubMed] Related Publications
S100A4 is a member of the S100 family of calcium-binding proteins that is directly involved in tumor metastasis. In the present study, we examined the potential role of S100A4 in metastasis in breast cancer and its relation with matrix metalloproteinase-13 (MMP-13). Analysis of 100 breast cancer specimens including 50 with and 50 without lymph node metastasis showed a significant upregulation of S100A4 and MMP-13 expression in metastatic breast cancer tissues. Positive immunoreactivity for S100A4 was associated with MMP-13 expression. Overexpression of S100A4 in the MDA-MB-231 breast cancer cell line upregulated MMP13 expression leading to increased cell migration and angiogenesis. SiRNA-mediated silencing of S100A4 downregulated MMP13 expression and suppressed cell migration and angiogenesis. Moreover, neutralization of MMP-13 activity with a specific antibody blocked cell migration and angiogenesis in MDA-MB-231/S100A4 cells. In vivo siRNA silencing of S100A4 significantly inhibited lung metastasis in transgenic mice. The present results suggest that the S100A4 gene may control the invasive potential of human breast cancer cells by modulating MMP-13 levels, thus regulating metastasis and angiogenesis in breast tumors. S100A4 could therefore be of value as a biomarker of breast cancer progression and a novel therapeutic target for human breast cancer treatment.

Related: Breast Cancer Angiogenesis and Cancer

Dmytriyeva O, Pankratova S, Owczarek S, et al.
The metastasis-promoting S100A4 protein confers neuroprotection in brain injury.
Nat Commun. 2012; 3:1197 [PubMed] Related Publications
Identification of novel pro-survival factors in the brain is paramount for developing neuroprotective therapies. The multifunctional S100 family proteins have important roles in many human diseases and are also upregulated by brain injury. However, S100 functions in the nervous system remain unclear. Here we show that the S100A4 protein, mostly studied in cancer, is overexpressed in the damaged human and rodent brain and released from stressed astrocytes. Genetic deletion of S100A4 exacerbates neuronal loss after brain trauma or excitotoxicity, increasing oxidative cell damage and downregulating the neuroprotective protein metallothionein I+II. We identify two neurotrophic motifs in S100A4 and show that these motifs are neuroprotective in animal models of brain trauma. Finally, we find that S100A4 rescues neurons via the Janus kinase/STAT pathway and, partially, the interleukin-10 receptor. Our data introduce S100A4 as a therapeutic target in neurodegeneration, and raise the entire S100 family as a potentially important factor in central nervous system injury.

Sekine H, Chen N, Sato K, et al.
S100A4, frequently overexpressed in various human cancers, accelerates cell motility in pancreatic cancer cells.
Biochem Biophys Res Commun. 2012; 429(3-4):214-9 [PubMed] Related Publications
S100A4, a member of the Ca(2+) dependent S100 protein family, is reported to associate with metastasis through regulation of the motility and invasiveness of cancer cells. A high level of S100A4 protein has been reported in a variety of cancers, including pancreatic cancer. However, its biological role in pancreatic carcinogenesis is largely unknown. We previously reported that S100A4 is frequently overexpressed and that RNAi-mediated knockdown induces apoptosis and suppression of cell growth, motility, and invasiveness. In this study, we analyzed the effects of forced expression of S100A4 in pancreatic cancer cell lines without S100A4-upregulation. We used two cell lines without upregulation of S100A4 (PCI-35 and PCI-43) as well as two cell lines with highly upregulated S100A4 as the control (MIA PaCa-2 and PAN-07-JCK). Cells did not show acceleration of their growth and invasiveness after forced expression of S100A4, but remarkable acceleration of cell motility was observed only in PCI-35 and PCI-43. We further performed microarray analyses using PCI-35 and PCI-43 with and without forced expression of S100A4 and identified 72 and 18 genes that were 2-fold or more upregulated or downregulated, respectively, in both cell lines after forced expression of S100A4. Our results suggest that S100A4 is crucial for cell motility in pancreatic cancer and that some downstream genes may play important roles in cell motility.

Related: Apoptosis Cancer of the Pancreas Pancreatic Cancer

Li N, Song MM, Chen XH, et al.
S100A4 siRNA inhibits human pancreatic cancer cell invasion in vitro.
Biomed Environ Sci. 2012; 25(4):465-70 [PubMed] Related Publications
OBJECTIVE: Pancreatic cancer is one of the most deadly cancers, which is characterized by its high metastatic potential. S100A4 is a major prometastatic protein involved in tumor invasion and metastasis which precise role in pancreatic cancer has not been fully investigated. We knocked down the S100A4 gene in the Bxpc-3 pancreatic cancer cell line via RNA interference to study the changes in cell behavior.
METHODS: Real-time polymerase chain reaction and western blotting were used to detect mRNA and protein expression levels of S100A4, matrix metalloproteinase (MMP)-2, E-cadherin and thrombospondin (TSP)-1. Transwell chambers were used to detect the migration and invasion abilities; a cell adhesion assay was used to detect adhesion ability; colony forming efficiency was used to detect cell proliferation; flow cytometry was used to detect apoptosis.
RESULTS: S100A4 mRNA expression was reduced to 17% after transfection with S100A4-siRNA, and protein expression had a similar trend. mRNA and protein expression of MMP-2 was reduced and that of E-cadherin and TSP-1 was elevated, indicating that S100A4 affects their expression. S100A4-silenced cells exhibited a marked decrease in migration and invasiveness and increased adhesion, whereas overall proliferation and apoptosis were not overtly altered.
CONCLUSION: S100A4 and its downstream factors play important roles in pancreatic cancer invasion, and silencing A100A4 can significantly contain the invasiveness of pancreatic cancer.

Related: Apoptosis MMP2 Cancer of the Pancreas Pancreatic Cancer

Kanojia D, Zhou W, Zhang J, et al.
Proteomic profiling of cancer stem cells derived from primary tumors of HER2/Neu transgenic mice.
Proteomics. 2012; 12(22):3407-15 [PubMed] Related Publications
Human epidermal growth factor receptor 2 (HER2) overexpression leads to mammary tumorigenesis and its elevated levels lead to increase in cancer stem cells (CSCs), invasion, and metastasis. CSCs are resistant to radiation/chemotherapeutic drugs and are believed to be responsible for recurrence/relapse of cancer. CSCs are isolated using flow cytometry based sorting, although reliable, this technology hinders the convenient identification of molecular targets of CSCs. Therefore to understand the molecular players of increased CSC through HER2 overexpression and to develop meaningful targets for combination therapy, we isolated and characterized breast CSCs through convenient tumorsphere culture. We identified the altered protein expression in CSC as compared to non-CSC using LC-MS/MS and confirmed those results using qRT-PCR and Western blotting. Ferritin heavy chain 1 (FTH1) was identified as a candidate gene, which is involved in iron metabolism and iron depletion significantly decreased the self-renewal of CSCs. We further performed in silico analysis of altered genes in tumorsphere and identified a set of genes (PTMA, S100A4, S100A6, TNXRD1, COX-1, COX-2, KRT14, and FTH1), representing possible molecular targets, which in combination showed a promise to be used as prognostic markers for breast cancer.

Further References

Bjørnland K, Winberg JO, Odegaard OT, et al.
S100A4 involvement in metastasis: deregulation of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in osteosarcoma cells transfected with an anti-S100A4 ribozyme.
Cancer Res. 1999; 59(18):4702-8 [PubMed] Related Publications
The biological function of the metastasis-associated gene S100A4 is not fully understood, although there is evidence indicating interactions between the gene product and the cytoskeleton. We have examined whether an association could exist between S100A4 and the regulation of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs). For these studies, three clones of a highly metastatic human osteosarcoma cell line (OHS) transfected with a hammerhead ribozyme directed against the S100A4 gene transcript were used. The clones demonstrated different expression levels of S100A4 and also different metastatic capacity. In the clone with the most prominent down-regulation of S100A4, the mRNA levels of MMP2, membrane type (MT) 1-MMP, and TIMP-1 were significantly reduced in exponentially growing cultures. Western blots, gelatin zymography, and ELISA showed similar expression patterns of MMPs and TIMPs at the protein level. In the clones with an intermediate expression of S100A4, reduced expression of MT1-MMP and TIMP-1 was detected, whereas the expression of MMP-2 was at the same level as in the control cells. In contrast to the other factors, TIMP-2 was up-regulated in all of the clones independent of the extent of ribozyme-induced down-regulation of S100A4. The transwell chamber assay demonstrated that the capacity of the ribozyme-transfected cells to cross uncoated filters was reduced, relative to control cells, according to the reduction in the S100A4 expression level. The clone with the lowest reduction in S100A4 did not demonstrate different motility compared with control cells, whereas transfectants with only 5% S100A4 mRNA showed a 50% reduction in motility. Interestingly, this trend was even more striking when the capacity to cross Matrigel-coated filters was analyzed, as all the clones demonstrated between 40 and 75% reduced invasion. It is concluded that S100A4 may exert its effect on metastasis formation not only by stimulating the motility of tumor cells but also by affecting their invasive properties through influencing the expression of MMPs and their endogenous inhibitors.

Related: Bone Cancers MMP1 MMP2 Osteosarcoma

Takenaga K, Nakanishi H, Wada K, et al.
Increased expression of S100A4, a metastasis-associated gene, in human colorectal adenocarcinomas.
Clin Cancer Res. 1997; 3(12 Pt 1):2309-16 [PubMed] Related Publications
The S100A4 gene (also known as pEL98/mts1/p9Ka/18A2/42A/calvasculin /FSP1/CAPL) encoding an S100-related calcium-binding protein is implied to be involved in the invasion and metastasis of murine tumor cells. In the present study, the expression of S100A4 in human colorectal adenocarcinoma cell lines (SW837, LoVo, DLD-1, HT-29, SW480, SW620, WiDr, and Colo201) and surgically resected neoplastic tissues was examined to investigate whether S100A4 plays a role in the invasion and metastasis of human tumor cells. Northern blot analysis using total RNA isolated from the adenocarcinoma cell lines revealed that five of the eight cell lines expressed substantial amounts of S100A4 mRNA. Normal colon fibroblasts (CCD-18Co) expressed little of the RNA. Using surgically resected specimens, it seemed that the amount of S100A4 mRNA in adenomas was nearly equal to that in normal colonic mucosa, whereas adenocarcinomas expressed a significantly higher amount of the RNA than did the adjacent normal colonic mucosa. Immunohistochemical analysis using formalin-fixed paraffin-embedded surgical specimens and monoclonal anti-S100A4 antibody demonstrated that none of 12 adenoma specimens were immunopositive, whereas 8 of 18 (44%) focal carcinomas in carcinoma in adenoma specimens and 50 of 53 (94%) adenocarcinoma specimens were immunopositive. Interestingly, the incidence of immunopositive cells increased according to the depth of invasion, and nearly all of the carcinoma cells in 14 metastases in the liver were positive. These results suggest that S100A4 may be involved in the progression and the metastatic process of human colorectal neoplastic cells.

Related: Monoclonal Antibodies Colorectal (Bowel) Cancer CDKN2A

Nakamura N, Takenaga K
Hypomethylation of the metastasis-associated S100A4 gene correlates with gene activation in human colon adenocarcinoma cell lines.
Clin Exp Metastasis. 1998; 16(5):471-9 [PubMed] Related Publications
The DNA methylation status of the metastasis-associated S100A4 gene in S100A4-positive and -negative human colon adenocarcinoma cell lines was examined. Northern and Western blot analyses revealed that HT-29, SW480, SW620, WiDr and Colo201 cells expressed S100A4, whereas SW837, LoVo and DLD-1 cells expressed little S100A4. Using CpG methylation-sensitive and -insensitive restriction enzymes and PCR-based methylation assay, it was found that the S100A4 gene in HT-29, SW480, SW620, WiDr and Colo201 cells, but not in SW837, LoVo and DLD-1 cells, was hypomethylated and that the hypomethylation of the second intron was correlated well with the expression of S100A4. 5-Aza-2'-deoxycytidine, an inhibitor of the eukaryotic DNA methyltransferase, induced the expression of the S100A4 gene in SW837, LoVo and DLD-1 cells, while it showed no effect on the expression of the gene in WiDr cells. These results indicate that hypomethylation of the S100A4 gene results in the expression of the gene in colon adenocarcinoma cells.

Related: Azacitidine

Takenaga K
Suppression of metastasis-associated S100A4 gene expression by gamma-interferon in human colon adenocarcinoma cells.
Br J Cancer. 1999; 80(1-2):127-32 [PubMed] Free Access to Full Article Related Publications
S100A4 belongs to the S100 subfamily of calcium-binding proteins and has been suggested to be directly involved in invasion and metastasis of rodent and human tumour cells. The present study demonstrates that interferon gamma (IFN-gamma), but not IFN-alpha and IFN-beta, down-regulates the S100A4 mRNA level in colon adenocarcinoma WiDr cells in time- and dose-dependent manners. The effect was not associated with any cytotoxicity and was specific for the S100A4 mRNA, since the levels of the S100A6 and GAPDH mRNAs were not significantly affected by the treatment. IFN-gamma also strongly suppressed the S100A4 mRNA expression in HT-29 cells, but weakly in Colo201 cells. Flow cytometric analysis revealed that the level of the IFN-gamma receptor expression in Colo201 cells was lower than that in WiDr and HT-29 cells, suggesting that the suppression of the S100A4 expression by IFN-gamma depends on the amount of cell surface IFN-gamma receptor protein. IFN-gamma had no effect on the transcription rate of the S100A4 gene but reduced the stability of the S100A4 mRNA. WiDr cells treated with IFN-gamma showed reduced motile ability, further supporting the assumption that the S100A4 gene product is involved in controlling cell motility.

Albertazzi E, Cajone F, Leone BE, et al.
Expression of metastasis-associated genes h-mts1 (S100A4) and nm23 in carcinoma of breast is related to disease progression.
DNA Cell Biol. 1998; 17(4):335-42 [PubMed] Related Publications
The murine 18A2/mts1 and its human homolog h-mts1 (S100A4), encoding a Ca2+-binding protein belonging to the S-100 family, are associated with high invasive and metastatic potentials of murine tumors, human tumor cell lines in vitro, and human tumors growing as xenografts. The nm23 is a putative metastasis-suppressor gene whose expression has been found to correlate inversely with the metastatic potential of some forms of human cancer. The products of both human genes alter cytoskeletal dynamics, with antagonistic effects. In view of the equivocal association of nm23 with the metastatic potential of human cancer, we suspected that the relative expression of h-mts1 and nm23 might reflect tumor progression more accurately than either of them alone. We describe here the expression of these genes in infiltrating ductal carcinomas of the breast and show that high h-mts1 expression is associated with metastatic spread to the regional lymph nodes. The expression of nm23 on its own did not show a statistically significant inverse correlation with nodal spread. However, the expression status of the two genes, taken together, correlated strongly with the occurrence of nodal metastases. Breast cancers with no detectable expression of h-mts1 were found to be estrogen and progesterone receptor positive. Expression of h-mts1 was not related to tumor differentiation. The clinical data, together with the state of expression of steroid receptors and the expression levels of h-mts1 and nm23 genes, were analyzed using artificial neural networks for accuracy in predicting nodal spread of the carcinomas. These analyses support the conclusion that, overall, h-mts1 expression appears to be associated with and indicative of more aggressive disease. Complemented with nm23, h-mts1 could provide a powerful marker of breast cancer prognosis.

Related: Breast Cancer NME1

Albertazzi E, Cajone F, Sherbet GV
Characterization of a splice variant of metastasis-associated h-mts1 (S100A4) gene expressed in human infiltrating carcinomas of the breast.
DNA Cell Biol. 1998; 17(12):1003-8 [PubMed] Related Publications
The h-mts1 (S100A4) is a member of the S100 gene family, coding for a calcium-binding protein. It is a metastasis-associated gene whose expression shows strong correlation with the proliferative potential and invasive and metastatic ability of cancers. In a proportion of human intraductal carcinomas of the breast, a shorter variant h-mts1 transcript (h-mts1v) of approximately 450 nucleotides is expressed. We have characterized the transcript using reverse transcriptase-polymerase chain reaction employing exon-specific oligonucleotides. We show here that the noncoding exon 1a/1b is lost in the variant cDNA. Exons 2 and 3, which code for the protein, seem to be present in the variant isoform. The RT-PCR products obtained using exons 2- and 3-specific oligonucleotides showed a high degree of sequence homology with exons 2 and 3 of the h-mts1 gene. The expression of the variant transcript could be influencing disease progression, albeit not as effectively as the normal unspliced h-mts1 transcript.

Related: Breast Cancer


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Cite this page: Cotterill SJ. S100A4, Cancer Genetics Web: http://www.cancerindex.org/geneweb/S100A4.htm Accessed: date

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