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S100A8 (S100 calcium binding protein A8)

Written2011-02Claus Kerkhoff, Saeid Ghavami
Dept VAC / IMCI, Helmholtz Centre for Infection Research, Inhoffenstr 7, D-38124 Braunschweig, Germany (CK); Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada (SG)

(Note : for Links provided by Atlas : click)


Alias (NCBI)60B8AG
HGNC (Hugo) S100A8
HGNC Alias symbP8
HGNC Previous nameCAGA
HGNC Previous namecalgranulin A
 S100 calcium-binding protein A8 (calgranulin A)
LocusID (NCBI) 6279
Atlas_Id 46446
Location 1q21.3  [Link to chromosome band 1q21]
Location_base_pair Starts at 153390032 and ends at 153391073 bp from pter ( according to hg19-Feb_2009)  [Mapping S100A8.png]
Local_order Distal to LOC645900, proximal to S100A7A (S100 calcium binding protein A7A).
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CRADD (12q22) / S100A8 (1q21.3)GPX3 (5q33.1) / S100A8 (1q21.3)S100A8 (1q21.3) / ANXA11 (10q22.3)
S100A8 (1q21.3) / C5orf58 (5q35.1)S100A8 (1q21.3) / MYO6 (6q14.1)S100A8 (1q21.3) / NAPA (19q13.32)
S100A8 (1q21.3) / S100A8 (1q21.3)


Note S100A8 belongs to the S100/calgranulin family of small non-ubiquitous cytoplasmic Ca2+-binding proteins of EF-hand type. The proteins were referred to "S100" because of their solubility in saturated ammonium sulphate solution. Sixteen of 21 members are localised in a cluster on human chromosome 1q21.
The clustered organization of these S100 genes is conserved during evolution (Ridinger et al., 1998). A comparison between man and mouse has shown that during evolution, the colinearity of the S100 gene cluster has been destroyed by some inversions. However, the colocalization of the myeloid expressed S100 genes such as S100A8, S100A9, and S100A12 is conserved. It has been speculated, that the structural integrity of that part of the locus is necessary for the coordinated expression of these genes (Nacken et al., 2001).
Remarkably, the S100 gene cluster is located in close proximity to a region which has been frequently rearranged in human cancer (Carlsson et al., 2005) and to the epidermal differentiation complex (EDC) (Mischke et al., 1996). EDC is a cluster of genes on chromosome 1q21 encoding proteins that fulfil important functions in terminal differentiation in the human epidermis, including filaggrin, loricrin and others. In addition, linkage analyses have identified a psoriasis susceptibility region, the PSORS4 locus, that is close to the S100 gene cluster (Hardas et al., 1996; Semprini et al., 2002). These data are important indications for the involvement of S100 genes in inflammatory as well as neoplastic disorders. It has been speculated that the rearrangements result in a deregulated expression of S100 genes associated with neoplasia.
Description The S100 gene structure has been structurally conserved during evolution. Similar to most S100 genes S100A8 consists of three exons that are separated by two introns.
Transcription In the S100A8 gene, exon 1 encodes the untranslated region. The protein is encoded by sequences in exon 2 and exon3, encoding a N-terminal and a C-terminal EF-hand motif, respectively.
The sequence of human S100A8 cDNA has an open reading frame of 279 nucleotides predicting a protein of 93 amino acids.
S100A8 expression appears to be restricted to a specific stage of myeloid differentiation. The protein is present in circulating neutrophils and monocytes, but not in resting tissue macrophages. In peripheral blood monocytes it is down regulated during maturation to macrophages. Despite a number of distinct regulatory regions are located upstream of the transcription initiation site, the corresponding nuclear factors as well as the underlying molecular mechanisms still remain unclear. Transcription factors such as PU.1 (Henkel et al., 2002), C/EBP-alpha and C/EBP-beta (Kuruto-Niwa et al., 1998) have been shown to drive S100 gene expression within the myeloid lineage.
Beside its expression in myeloid cells S100A8 is expressed in epithelia under specific conditions. Its expression is transiently induced in keratinocytes after epidermal injury and UVB irradiation, and the protein is expressed at extremely high levels in psoriatic keratinocytes. Furthermore, its expression is induced by pro-inflammatory cytokines such as TNFalpha and IL1beta. Recently, a complex of Poly (ADP-ribose) polymerase (PARP-1) and Ku70/Ku80 has been demonstrated to drive the stress response-specific S100 gene expression (Grote et al., 2006). The stress response-induced expression of the S100 proteins points to an important role in skin pathology.
Pseudogene Not known.


  Gene: Box = exon (light blue = 5'UTR, yellow = CDS, red = 3'UTR); Line = intron.
Protein: Upper boxes, alternating colours: exons (coding part only). Lower boxes: protein domains. Green box = not structure; blue box = helix; violett box = calcium-binding domain.
Description The sequence of human S100A8 cDNA has an open reading frame of 279 nucleotides predicting a protein of 93 amino acids and a calculated Mr of 10835 Da. The theoretical isoelectric point is 6.6.
S100A8 is composed of two helix-loop-helix EF-hand motifs. The C-terminal EF-hand contains a canonical Ca2+-binding loop of 12 amino acids. Conversely, the N-terminal EF-hand contains a Ca2+-binding loop of 14 residues that binds Ca2+ mostly through main-chain carbonyl groups that which is specific to S100 proteins. Consequently, S100 proteins have a weaker Ca2+ affinity than typical Ca2+ sensors such as calmodulin (Donato, 2003).
In vivo and in vitro experiments have shown that S100 proteins form homo-, hetero- and oligomeric assemblies (Hunter and Chazin, 1998; Osterloh et al., 1998; Pröpper et al., 1999; Moroz et al., 2003). Together with their specific cell- and tissue-expression patterns, the structural variations, and the different metal ion binding properties (Ca2+, Zn2+ and Cu2+) the S100 protein complexes might be functionally diversified. S100A8 preferentially interacts with S100A9.
It is worthwhile mentioning that the murine analogs display a stronger tendency to form homodimeric protein complexes. In view of the formation of different tertiary structures with putative distinct functions it is tempting to speculate that S100A8 and/or A9 have different functions in mouse and man.
Expression S100A8 is mainly expressed in cells of the myeloid lineage, however, its gene expression is induced in epithelial cells in response to stress, in specific conditions such as wound healing, UV exposition, abundant in psoriasis keratinocytes, differentially expressed in several cancers.
Localisation Mostly cytoplasmic, but also at membranes and cytoskeleton.
In resting phagocytes the S100A8/A9 protein complex is mainly located in the cytosol. Upon cellular activation the protein complex is either translocated to cytoskeleton and plasma membrane or released into the extracellular environment.
The translocation pathways occur upon the elevation of the intracellular calcium level (Roth et al., 1993). At a later time point, the S100A8/A9 heterodimers can be detected on the surface of monocytes (Bhardwaj et al., 1992). The mechanism by which the S100A8/A9 heterodimer penetrates the plasma membrane remains unclear since the S100 proteins lack a transmembrane signaling region.
The secretion pathway relies on the activation of protein kinase C. This pathway differs from the classical as well as the alternative secretion pathways of cytokines (Moqbel and Coughlin, 2006). It has been demonstrated that this novel secretion pathway is energy-consuming and depends on an intact microtubule network (Murao et al., 1990; Rammes et al., 1997).
Recent investigations give evidence that interaction of S100A8/A9 with annexin-6 is involved in surface expression and release of S100A8/A9 (Bode et al., 2008). Annexins are another class of Ca2+-regulated proteins. They are characterized by the unique architecture of their Ca2+-binding sites, which enables them to peripherally dock onto negatively charged membrane surfaces in their Ca2+-bound conformation. This property links annexins to many membrane-related events such as certain exocytic and endocytic transport steps. This is an interesting finding since S100A8 and S100A9 are expressed in cancerous cells of secretory tissues as breast and prostate. Cells originating from such glandular tissues are rich in membrane structures, suggesting that membrane-associated molecular targets for the S100A8/A9 proteins could be potentially found in these cells.
Recent investigations also demonstrated the association of S100A8/A9 with cholesterol-enriched membrane microdomains (lipid rafts) (Nacken et al., 2004). This observation is in agreement with the enhancing effect of S100A8/A9 on NADPH oxidase since the formation of the oxidase complex takes place at lipid rafts.
Function Intra- as well as extracellular roles have been proposed for the S100 proteins.

Intracellular activities of S100A8/A9
In the intracellular milieu, S100 proteins are considered as calcium sensors changing their conformation in response to calcium influx and then mediating calcium signals by binding to other intracellular proteins. In a mouse knock-out model chemokine-induced down regulation of the cytosolic Ca2+-level was detected (Nacken et al., 2005).
After calcium binding, the S100A8/A9 protein complex binds specifically polyunsaturated fatty acids. S100A8/A9 represents the exclusive arachidonic acid-binding capacity in the neutrophil cytosol (Kerkhoff et al., 1999), and participates in NADPH oxidase activation by transferring arachidonic acid to membrane-bound gp91phox during interactions with two cytosolic oxidase activation factors, p67phox and Rac-2. The functional relevance of S100A8/A9 in the phagocyte NADPH oxidase activation was demonstrated by the impairment of NADPH oxidase activity in neutrophil-like NB4 cells, after specifically blocking S100A9 expression, and employing bone marrow-derived PMNs from S100A9-/- mice (Kerkhoff et al., 2005).
In accordance to their role in myeloid cells, S100A8/A9 enhances epithelial NADPH oxidases (Benedyk et al., 2007). As a consequence of enhanced ROS levels, NF-kB activation and subsequently TNF-alpha and IL-8 mRNA levels are increased in S100A8/A9-HaCaT keratinocytes, consistent with the view that NF-kB is a redox-sensitive transcription factor. Further consequences of S100A8/A9-mediated NF-kB activation are reduced cell growth, increased expression of differentiation markers, and enhanced PARP cleavage as an indicator of increased cell death (Voss et al., 2011).
In view of the stress response-induced expression of the two S100 proteins in keratinocytes these findings have great implications for tissue remodeling and repair. For example, keratinocytes acquire an activated state after cutaneous wounding in which proliferation is favored over differentiation in order to replenish the lost material and rapidly close the site of injury. Thus, it is likely to hypothesize that S100A8/A9-mediated growth reduction is required for the upcoming cell fate decision of damaged cells, i.e. for a survival phase to be followed by differentiation, proliferation, or apoptosis. These data have also an impact on tumorigenesis since S100 gene expression is associated with neoplastic disorders.
In migrating monocytes the S100A8/A9 complex has been found to be associated with cytoskeletal tubulin and to modulate transendothelial migration (Vogl et al., 2004). Investigations using two different mouse knock-out models demonstrated no obvious phenotype (Manitz et al., 2003; Hobbs et al., 2003). However, reduced migration of S100A9-deficient neutrophils and decreased surface expression of CD11b, which belongs to the integrin family, were observed upon in vitro stimulation.

Extracellular activities of S100A8/A9
The S100/calgranulins display antimicrobial activity by depriving bacterial pathogens of essential trace metals such as Zn2+ and Mn2+ (Steinbakk et al., 1990; Murthy et al., 1993; Clohessy and Golden, 1995; Sohnle et al., 2000). In the context of inflammation, it has been proposed that S100A8/A9 is massively released when neutrophils die to provide a growth-inhibitory type of host defense that is adjunctive to the usual microbicidal functions by binding metals other than Ca2+ (Corbin et al., 2008).
In addition, S100/calgranulins serve as leukocyte chemoattractants (Lackmann et al., 1992; Lackmann et al., 1993; Kocher et al., 1996; Lim et al., 2008). Murine S100A8 has potent chemotactic activity for neutrophils and monocytes in vitro and in vivo (Lackmann et al., 1992). In contrast, human S100A8 displays only weak leukocyte chemotactic activity in vitro and in vivo (Lackmann et al., 1993). Detailed analysis revealed that the hinge region contributes to the chemotactic activity of murine, but not human S100A8. These data questioned whether the proteins are orthologs since there is a high degree of homology between murine and human S100A8 but a functional divergence. Intriguingly, human S100A12 is chemotactic and the hinge region of human S100A12 has been implicated herein (Yang et al., 2001). Thus, the functional and sequence divergence suggested complex evolution of the S100 family in mammals.
The putative pro-inflammatory functions of S100A8 and S100A9 have recently been investigated in two different mouse knock-out models. S100A9 deficiency did not result in an obvious phenotype (Manitz et al., 2003; Hobbs et al., 2003). However, reduced migration of S100A9-deficient neutrophils and decreased surface expression of CD11b, which belongs to the integrin family, were observed upon in vitro stimulation. In addition, chemokine-induced down regulation of the cytosolic Ca2+-level was detected. Obviously, these in vitro effects are compensated by alternative pathways in vivo.
Remarkably, cancer cells utilize S100A8 and S100A9 as guidance for the adhesion and invasion of disseminating malignant cells (Hiratsuka et al., 2006). In the context of malignancy it was reported that S100A8/A9 attracts Mac-1+ myeloid cells to the lung tissue. Recruited Mac-1+ myeloid cells in lung in turn produce S100A8/A9 in response to primary malignant cells in a so called "premetastatic phase". This phase shows the general characteristics of an inflammation state which facilitates the micro-environmental changes required for the migration and implantation of primary tumor cells to lung tissue. After preparation of the target tissue for accepting the malignant cells, tumor cells mimic Mac-1+ myeloid cells in response to S100A8/A9 chemotactic signaling and migrate to lung. So, it seems that tumor cells and Mac-1+ myeloid cells utilize a common pathway for migration to lung which involves the activation of RAGE) (Srikrishna and Freeze, 2009).
The S100/calgranulins display cytokine-like functions, including activation of the receptor for advanced glycation endproducts (RAGE) (Hofmann et al., 1999; Herold et al., 2007). RAGE is a member of the immunoglobulin superfamily and present on numerous cell types. It has been shown to play crucial roles in a variety of pathophysiological situations, such as wound healing, atherosclerotic lesion development, tumor growth and metastasis, systemic amyloidosis, and Alzheimer disease (Bierhaus et al., 2005). RAGE/S100 interaction has been considered a very attractive model to explain how RAGE and its proinflammatory ligand contribute to the pathophysiology of several inflammatory diseases.
Beside the above mentioned receptors a number of other cell surface binding sites specific for S100A8/A9 have been reported, such as novel carboxylated glycans (Srikrishna et al., 2001), heparan sulfate glycosaminoglycans (Robinson et al., 2002), beta2-integrin (Newton and Hogg, 1998), and the fatty acid transporter FAT/CD36 (Kerkhoff et al., 2001). Therefore, the cell surface receptor of S100A8/A9 is still in debate.
Interestingly, the growth-stimulatory activity of S100A8/A9 has been demonstrated to be mediated by binding to the receptor of advanced glycation end products (RAGE) (Ghavami et al., 2008b; Turovskaya et al., 2008; Gebhardt et al., 2008). It is likely to speculate that the selective up-regulation of S100 proteins may be of importance for survival and proliferation of metastasizing cancer cells.
S100A8/A9 complexes that are secreted from phorbolester-stimulated neutrophil-like HL-60 cells have been shown to carry the eicosanoid precursor arachidonic acid (Kerkhoff et al., 1999). The S100A8/A9-arachidonic acid complex is recognized by the fatty acid transporter FAT/CD36, and the fatty acid is rapidly taken up (Kerkhoff et al., 2001). Endothelial cells as well as neutrophils themselves utilize both endogenous and exogenous arachidonic acid for transcellular production of eicosanoids (Sala et al., 1999). Therefore, the secreted S100A8/A9-AA complex may serve as a transport protein to move AA to its target cells. This may represent a mechanism by which AA-derived eicosanoids are synthesized in a cooperative manner between different cell species due to environmental cues.
S100A8/A9 displays apoptosis-inducing activity against various tumor cells (Yui et al., 1995; Yui et al., 2002; Ghavami et al., 2004; Ghavami et al., 2008a; Kerkhoff and Ghavami, 2009; Ghavami et al., 2009; Ghavami et al., 2010). It was speculated that this activity was due to the ability to bind divalent metal ions including Zn2+, Mn2+ and Cu2+ at sites that are distinct from Ca2+-binding sites. However, a number of recent reports now indicate that S100A8/A9 exerts its activity by both chelation of trace metal ions such as Zn2+ and cell surface receptor mediated pathways.
Although a number of receptors have been shown to bind S100A8/A9, the nature of the receptor involved in S100A8/A9-induced cell death remains to be elucidated. Experiments with certain cell lines either deficient for or over expressing components of the death signaling machinery as well as RAGE gene silencing and blocking RAGE-specific antibody approaches excluded both RAGE and the classical death receptor to be involved in S100A8/A9-induced cell death, even though S100A8/A9 can specifically bind to cancer cells and RAGE mediates the growth-promoting activity obvious at low micromolar concentrations of S100A8/A9. Clearly, investigations to identify the receptor involved in S100A8/A9-induced cell death are critical.

Homology Overall, the S100 proteins share significant sequential homology in the EF-hand motifs, but are least conserved in the hinge region. This region is proposed to provide for specific interaction with target proteins (Groves et al., 1998; Zimmer et al., 2003; Santamaria-Kisiel et al., 2006; Fernandez-Fernandez et al., 2008; van Dieck et al., 2009). The availability of high-resolution S100-target structures has highlighted important structural features that contribute to S100 protein functional specificity (Bhattacharya et al., 2003).
The functional diversification of S100 proteins is achieved by their specific cell- and tissue-expression patterns, structural variations, different metal ion binding properties (Ca2+, Zn2+ and Cu2+) as well as their ability to form homo-, hetero- and oligomeric assemblies (Hunter and Chazin, 1998; Osterloh et al., 1998; Pröpper et al., 1999; Tarabykina et al., 2001; Moroz et al., 2003; Fritz et al., 2010). Although the function of S100 proteins in cancer cells in most cases is still unknown, the specific expression patterns of these proteins are a valuable diagnostic tool.

Implicated in

Entity General note
Note Comparative and functional genomics have revealed that a number of S100 proteins are found to be differentially expressed in cancer cells. Several of these have been associated with tumor development, cancer invasion or metastasis in recent studies (for review see Salama et al., 2008).
S100A8 and S100A9 are abundant in cells of the myeloid lineage, are released from activated phagocytes and display intra- and extracellular functions. Their expression is ubiquitously observed in the squamous epithelia under normal, inflammatory and cancerous conditions. Immunohistochemical investigations have shown that the S100 proteins are over expressed in skin cancers, pulmonary adenocarcinoma, pancreatic adenocarcinoma, bladder cancers, ductal carcinoma of the breast, and prostate adenocarcinoma. In contrast, S100A8 and S100A9 are down-regulated in esophageal squamous cell carcinomas. Furthermore, plasma levels of S100A8/A9 are elevated in patients suffering from various cancers. Insofar, S100A8 and S100A9 might represent novel diagnostic markers for some carcinomas.
S100A8 and S100A9 have been suggested to have potential roles in carcinogenesis and tumor progression. However, the biological role of S100A8/A9 remains to be elucidated. It is conceivable that S100A8 and S100A9 modulate signal pathways to directly promote invasion, migration and metastasis, probably via activation of NF-kB, Akt or MAP kinases.
In the last decade the concept of the functional relationship between inflammation and cancer has been developed that is based on numerous findings, ranging from epidemiological studies to molecular analyses of mouse models (Coussens and Werb, 2002). In this concept, the generation of an inflammatory microenvironment supports tumorigenesis by promoting cancer cell survival, proliferation, migration, and invasion. Although it is clear that inflammation alone does not cause cancer, it is evident that an environment that is rich in inflammatory cells, growth factors, activated stroma, and DNA-damage-promoting agents certainly potentiates and/or promotes neoplastic risk. In addition, many cancers arise from sites of infection, chronic irritation and inflammation.
Recent data have expanded our knowledge demonstrating that specific soluble factors released from primary tumors induce the S100A8 and S100A9 gene expression in the target tissue. After secretion S100A8 and S100A9 might display chemokine- and cytokine-like properties that promote invasion, migration and metastasis. These data indicate that tumor cells are able to reprogram some of the signaling molecules of the innate immune system. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.
Entity Skin cancer
Note The expression of S100A8 and S100A9 in epithelial cells was first detected in the squamous epithelia (Gabrielsen et al., 1986). Normal S100A8 and S100A9 are expressed at minimal levels in the epidermis. However, their expression is induced in inflammatory and cancerous conditions, and pro-inflammatory cytokines such as TNF-alpha and IL1 beta are involved herein.
Gene expression analysis in a mouse model of chemically induced skin carcinogenesis identified a large set of novel tumor-associated genes including S100A8 (Hummerich et al., 2006). The data was confirmed by in situ hybridization and immunofluorescence analysis on mouse tumor sections, in mouse keratinocyte cell lines that form tumors in vivo, and in human skin tumor specimens.
However, conflicting results have been published concerning S100 expression in skin cancer. For instance, esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide. DNA microarray data analysis revealed that S100A8 and S100A9 were significantly down regulated in human ESCC versus the normal counterparts (Zhi et al., 2003). Interestingly, among the 42 genes either up regulated or down regulated in tumors, as compared to normal esophageal squamous epithelia, nine of the altered expression genes were related to arachidonic acid (AA) metabolism, suggesting that AA metabolism pathway and its altered expression may contribute to esophageal squamous cell carcinogenesis. Similar data were obtained by Ji et al. (2004). They investigated the differential expression of the S100 gene family at the RNA level in human ESCC. Eleven out of 16 S100 genes were significantly down regulated in ESCC versus the normal counterparts. Only the
Entity Lung adenocarcinomas
Note S100A9 over expression has been detected in various carcinomas of glandular cell origin, and its expression has been associated with poor tumor differentiation. Similarly, S100A9 immunopositivity was also detected in pulmonary adenocarcinoma cell lines and resected pulmonary adenocarcinoma (Arai et al., 2001). Examination of the relation of S100A9 expression to tumor differentiation showed that the expression rate in pulmonary adenocarcinoma showed higher correlation in poorly differentiated carcinomas.
Another study confirmed these data (Su et al., 2010). Immunohistochemical staining of both S100 proteins showed a significant up-regulation in lung cancer tissue, and quantitative PCR revealed significantly higher levels of S100A8 and S100A9 mRNA transcripts in lung cancer tissues. Moreover, this study correlates S100A9 expression with inflammation and other clinical features (Su et al., 2010).
Primary tumors influence the environment in the lungs before metastasis. They release specific soluble factors that prepare the premetastatic niche for the engraftment of tumor cells. In several studies it has been shown that tumor cells induce both expression and secretion of S100A8 and S100A9 in the target organ that display a promoting role in cancer cell survival, proliferation, migration, and invasion (Hiratsuka et al., 2002; Hiratsuka et al., 2006; Hiratsuka et al., 2008; Saha et al., 2010).
Microarray analysis of lungs from tumor-bearing and non-bearing mice revealed the strong up-regulation of a number of genes including S100A8 and S100A9 (Hiratsuka et al., 2002). Their expression in Mac 1+-myeloid cells and endothelial cells was induced by factors such as vascular endothelial growth factor A (VEGF-A), tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta), both in vitro and in vivo (Hiratsuka et al., 2006). Remarkably, anti-S100A8 neutralizing antibody treatment blocked metastasis. S100A8 and S100A9 were shown to induce the expression of serum amyloid A (SAA) that attracted Mac 1+-myeloid cells in the premetastatic lung (Hiratsuka et al., 2008). These studies demonstrated that lung cancer cells utilize S100A8 and S100A9 as guidance for the adhesion and invasion of disseminating malignant cells.
Entity Pancreatic adenocarcinoma
Note Patients with ductal adenocarcinoma of the pancreas have a dismal prognosis. Thus, there is an urgent need for early detection markers and the development of immunotherapeutical approaches concentrating on the induction and enhancement of immune responses against tumors. Proteomic analyses of pancreatic adenocarcinoma, normal adjacent tissues, pancreatitis, and normal pancreatic tissues revealed a number of differentially expressed genes (Shen et al., 2004). S100A8 was found to be specifically over expressed in tumors compared with normal and pancreatitis tissues.
These data are in accordance with another study (Sheikh et al., 2007). Strong expression of S100A8 and S100A9 was found in tumor-associated stroma but not in benign or malignant epithelia. Further analyses identified stromal CD14+ CD68- monocytes/macrophages as source for S100 expression. Interestingly, the number of S100A8-positive cells in the tumor microenvironment negatively correlated with the expression of the tumor suppressor protein, Smad4. The number of S100A9-positive cells was not altered in Smad4-negative or Smad4-positive tumors.
A similar correlation was found in colorectal cancer tumors (Ang et al., 2010). The number of stromal S100A8- and S100A9-positive cells was associated with the presence or absence of Smad4. Smad4-negative tumors showed enhanced numbers of S100A8/A9 stroma cells, and the corresponding patients had a poor survival prognosis. Investigation of the underlying molecular mechanisms revealed that both migration and proliferation was enhanced in response to exogenous S100A8 and S100A9, irrespective of Smad4-presence. However, depletion of Smad4 resulted in loss of responsiveness to exogenous S100A8, but not S100A9. Vice versa, Smad4 expression in Smad4-negative cells enhanced the responsive-ness to S100A8 and S100A9. Further analyses give evidence that similar to TGF-beta, S100A8 and S100A9 induce the phosphorylation of both Smad2 and Smad3 that was blocked by a RAGE-specific antibody. These data point to a functional re
Entity Bladder cancers
Note Gene expression profiles revealed that thirteen members of the S100 gene family were differentially expressed in human bladder cancers. S100A8 and S100A9 were found to be over expressed (Yao et al., 2007).
Another study investigated S100A9 expression and DNA methylation in urothelial cancer cell lines and cancer tissue (Dokun et al., 2008). Expression of S100A9 was found to be generally elevated in the tumor tissues but S100A9 was weakly expressed in most cancer cell lines. The S100A9 promoter contains 6 CpG sites, and its methylation state was unrelated to the variable expression. It has been hypothesized that over expression of genes is the consequence of DNA hypomethylation, however, DNA methylation and gene expression are less strictly related for those genes having promoters within CpG-islands. Alternatively, the increased S100A9 gene expression may be related to that of other immune-related genes in the carcinoma cell cultures. This is sustained by the facts that S100A9 is secreted by epithelial and other cell types to modulate inflammatory reactions as well as to promote cancer proliferation and metastasis.
Two recent studies propose S100A8 and S100A9 gene expression as prognostic value for bladder cancer (Minami et al., 2010; Ha et al., 2010). By proteomic analysis of pre- and postoperative sera from bladder cancer patients S100A8 and S100A9 were identified as tumor-associated proteins (Minami et al., 2010). Interestingly, S100A8 expression was associated with bladder wall muscle invasion of the tumor and cancer-specific survival while S100A9 expression was associated with the tumor grade. In addition, the expression of both proteins S100A8/A9 was correlated with recurrence-free survival.
In another study it was evaluated whether S100A8 is a prognostic value for non-muscle-invasive bladder cancer (NMIBC) (Ha et al., 2010). S100A8 expression was evaluated in a total of 103 primary NMIBC samples by quantitative PCR. The mRNA expression levels of S100A8 were significantly related to the progression of NMIBC, suggesting that S100A8 might be a useful prognostic marker for disease progression of NMIBC.
Entity Breast cancers
Note S100A8 and S100A9 are expressed in breast cancers (Cross et al., 2005), especially in invasive breast carcinoma (Arai et al., 2004). By immunohistochemical analyses a strong S100A9 immunoreactivity has been demonstrated in invasive as well as non-invasive ductal carcinoma. No immunopositive reaction was observed in invasive lobular carcinomas, and no significant differences were detected in the number of myelomonocytic cells expressing S100A9. These data give evidence that S100A9 in glandular epithelial cells is newly expressed under cancerous conditions and is over-expressed in poorly differentiated adenocarcinoma (Arai et al., 2004). Further analyses target on the relationship between S100A8/A9 expression and pathological parameters that reflect the aggressiveness of carcinoma. The immunopositivity for S100A8/A9 correlated with poor tumor differentiation, mitotic activity, HER2/neu over expr By analyses of ductal carcinoma in situ and invasive ductal carcinoma of the breast S100A9 has been demonstrated to be most abundantly expressed in the invasive tumor (Seth et al., 2003). Therefore, the expression of S100A8 and S100A9 has been correlated with the degree of noninvasive / invasive behavior. There are conflicting data concerning this correlation. For instance, non-invasive MCF-7 breast cancer cells do not express S100A9, and its gene expression is induced by cytokine oncostatin M through the STAT3 signaling cascade (Li et al., 2004). However, non-invasive MDA-MB-468 cells are abundant for both S100 proteins (Bode et al., 2008) and invasive breast cancer cells MDA-MB-231 show low transcript level of S100A9 (Nagaraja et al., 2006).
Entity Thyroid carcinoma
Note Similar to other carcinomas of glandular cell origin, expression of S100A8 and S100A9 is significantly linked to dedifferentiation of thyroid carcinoma (Ito et al., 2005; Ito et al., 2009). S100A8 and S100A9 immunreactivity was found in all undifferentiated carcinomas examined, while papillary carcinoma, follicular carcinoma, follicular adenoma and medullary carcinoma and normal follicules were negative for both proteins. Further analyses revealed that S100A9 is a useful marker for discriminating intrathyroid epithelial tumor from squamous cell carcinoma or undifferentiated carcinoma with squamoid component (Ito et al., 2006).
Entity Prostate cancer
Note Increased levels of S100A8, S100A9, and RAGE have been reported in prostatic intra epithelial neoplasia and preferentially in high-grade adenocarcinomas, whereas benign tissue was negative or showed weak expression of the proteins. The three proteins showed a strong overlap in the expression pattern. S100A9 serum level was significantly elevated in cancer patients compared with benign prostatic hyperplasia patients or healthy individuals. Therefore, S100A8 and S100A9 might represent novel diagnostic markers for prostate cancer and benign prostate hyperplasia (Hermani et al., 2005).
In further analyses it has been demonstrated that S100A8 and S100A9 are secreted by prostate cancer cells, and extracellular S100A8/A9 stimulates migration of benign prostatic cells in vitro by activation of NF-kB and increased phosphorylation of p38 and p44/p42 MAP kinases. Immunofluorescence analyses give evidence for a RAGE-mediated response (Hermani et al., 2006).
The significance of being diagnostic markers for prostate cancer has been questioned by Ludwig et al. (2007). Their re-evaluation study has shown that S100A8/A9 did not improve the differentiation between patients with and without prostate cancer. The data give no evidence for the replacement of the established marker PSA by S100A8/A9.


Smad4 loss is associated with fewer S100A8-positive monocytes in colorectal tumors and attenuated response to S100A8 in colorectal and pancreatic cancer cells.
Ang CW, Nedjadi T, Sheikh AA, Tweedle EM, Tonack S, Honap S, Jenkins RE, Park BK, Schwarte-Waldhoff I, Khattak I, Azadeh B, Dodson A, Kalirai H, Neoptolemos JP, Rooney PS, Costello E.
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PMID 20622003
S100A8 and S100A9 overexpression is associated with poor pathological parameters in invasive ductal carcinoma of the breast.
Arai K, Takano S, Teratani T, Ito Y, Yamada T, Nozawa R.
Curr Cancer Drug Targets. 2008 Jun;8(4):243-52.
PMID 18537548
S100A9 expression in invasive ductal carcinoma of the breast: S100A9 expression in adenocarcinoma is closely associated with poor tumour differentiation.
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This paper should be referenced as such :
Kerkhoff, C ; Ghavami, S
S100A8 (S100 calcium binding protein A8)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(9):735-745.
Free journal version : [ pdf ]   [ DOI ]

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(1;6)(q21;q14) S100A8/MYO6

External links

HGNC (Hugo)S100A8   10498
Entrez_Gene (NCBI)S100A8  6279  S100 calcium binding protein A8
Aliases60B8AG; CAGA; CFAG; CGLA; 
CP-10; L1Ag; MA387; MIF; MRP8; NIF; P8
GeneCards (Weizmann)S100A8
Ensembl hg19 (Hinxton)ENSG00000143546 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000143546 [Gene_View]  ENSG00000143546 [Sequence]  chr1:153390032-153391073 [Contig_View]  S100A8 [Vega]
ICGC DataPortalENSG00000143546
TCGA cBioPortalS100A8
AceView (NCBI)S100A8
Genatlas (Paris)S100A8
SOURCE (Princeton)S100A8
Genetics Home Reference (NIH)S100A8
Genomic and cartography
GoldenPath hg38 (UCSC)S100A8  -     chr1:153390032-153391073 -  1q21.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)S100A8  -     1q21.3   [Description]    (hg19-Feb_2009)
GoldenPathS100A8 - 1q21.3 [CytoView hg19]  S100A8 - 1q21.3 [CytoView hg38]
genome Data Viewer NCBIS100A8 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AA401538 AA903259 AI126134 AK291328 BC005928
RefSeq transcript (Entrez)NM_001319196 NM_001319197 NM_001319198 NM_001319201 NM_002964
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)S100A8
Alternative Splicing GalleryENSG00000143546
Gene ExpressionS100A8 [ NCBI-GEO ]   S100A8 [ EBI - ARRAY_EXPRESS ]   S100A8 [ SEEK ]   S100A8 [ MEM ]
Gene Expression Viewer (FireBrowse)S100A8 [ Firebrowse - Broad ]
GenevisibleExpression of S100A8 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6279
GTEX Portal (Tissue expression)S100A8
Human Protein AtlasENSG00000143546-S100A8 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP05109   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP05109  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP05109
Splice isoforms : SwissVarP05109
Domaine pattern : Prosite (Expaxy)EF_HAND_1 (PS00018)    EF_HAND_2 (PS50222)    S100_CABP (PS00303)   
Domains : Interpro (EBI)EF-hand-dom_pair    EF_Hand_1_Ca_BS    EF_hand_dom    S100/CaBP-9k_CS    S100_Ca-bd_sub    S100A8   
Domain families : Pfam (Sanger)S_100 (PF01023)   
Domain families : Pfam (NCBI)pfam01023   
Domain families : Smart (EMBL)S_100 (SM01394)  
Conserved Domain (NCBI)S100A8
DMDM Disease mutations6279
Blocks (Seattle)S100A8
PDB (RSDB)1MR8    1XK4    4GGF    4XJK    5HLO    5HLV    5W1F    6DS2   
PDB Europe1MR8    1XK4    4GGF    4XJK    5HLO    5HLV    5W1F    6DS2   
PDB (PDBSum)1MR8    1XK4    4GGF    4XJK    5HLO    5HLV    5W1F    6DS2   
PDB (IMB)1MR8    1XK4    4GGF    4XJK    5HLO    5HLV    5W1F    6DS2   
Structural Biology KnowledgeBase1MR8    1XK4    4GGF    4XJK    5HLO    5HLV    5W1F    6DS2   
SCOP (Structural Classification of Proteins)1MR8    1XK4    4GGF    4XJK    5HLO    5HLV    5W1F    6DS2   
CATH (Classification of proteins structures)1MR8    1XK4    4GGF    4XJK    5HLO    5HLV    5W1F    6DS2   
Human Protein Atlas [tissue]ENSG00000143546-S100A8 [tissue]
Peptide AtlasP05109
Protein Interaction databases
IntAct (EBI)P05109
Complex Portal (EBI)P05109 CPX-37 Calprotectin heterotetramer
P05109 CPX-39 Calprotectin heterodimer
P05109 CPX-42 S100A8 complex
P05109 CPX-42 S100A8 complex
P05109 CPX-52 iNOS-S100A8/A9 complex
Ontologies - Pathways
Ontology : AmiGOcytokine production  toll-like receptor signaling pathway  leukocyte migration involved in inflammatory response  acute inflammatory response  chronic inflammatory response  positive regulation of peptide secretion  calcium ion binding  protein binding  extracellular region  extracellular region  extracellular space  extracellular space  nucleus  cytosol  cytosol  cytoskeleton  plasma membrane  autophagy  apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  inflammatory response  microtubule binding  zinc ion binding  response to zinc ion  astrocyte development  peptidyl-cysteine S-nitrosylation  antimicrobial humoral response  positive regulation of cell growth  neutrophil chemotaxis  sequestering of zinc ion  response to lipopolysaccharide  chemokine production  secretory granule lumen  autocrine signaling  Toll-like receptor 4 binding  wound healing  defense response to bacterium  neutrophil degranulation  innate immune response  intermediate filament cytoskeleton  response to ethanol  arachidonic acid binding  positive regulation of inflammatory response  RAGE receptor binding  defense response to fungus  positive regulation of NF-kappaB transcription factor activity  regulation of cytoskeleton organization  collagen-containing extracellular matrix  extracellular exosome  neutrophil aggregation  positive regulation of intrinsic apoptotic signaling pathway  
Ontology : EGO-EBIcytokine production  toll-like receptor signaling pathway  leukocyte migration involved in inflammatory response  acute inflammatory response  chronic inflammatory response  positive regulation of peptide secretion  calcium ion binding  protein binding  extracellular region  extracellular region  extracellular space  extracellular space  nucleus  cytosol  cytosol  cytoskeleton  plasma membrane  autophagy  apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  inflammatory response  microtubule binding  zinc ion binding  response to zinc ion  astrocyte development  peptidyl-cysteine S-nitrosylation  antimicrobial humoral response  positive regulation of cell growth  neutrophil chemotaxis  sequestering of zinc ion  response to lipopolysaccharide  chemokine production  secretory granule lumen  autocrine signaling  Toll-like receptor 4 binding  wound healing  defense response to bacterium  neutrophil degranulation  innate immune response  intermediate filament cytoskeleton  response to ethanol  arachidonic acid binding  positive regulation of inflammatory response  RAGE receptor binding  defense response to fungus  positive regulation of NF-kappaB transcription factor activity  regulation of cytoskeleton organization  collagen-containing extracellular matrix  extracellular exosome  neutrophil aggregation  positive regulation of intrinsic apoptotic signaling pathway  
REACTOMEP05109 [protein]
REACTOME PathwaysR-HSA-6799990 [pathway]   
NDEx NetworkS100A8
Atlas of Cancer Signalling NetworkS100A8
Wikipedia pathwaysS100A8
Orthology - Evolution
GeneTree (enSembl)ENSG00000143546
Phylogenetic Trees/Animal Genes : TreeFamS100A8
Homologs : HomoloGeneS100A8
Homology/Alignments : Family Browser (UCSC)S100A8
Gene fusions - Rearrangements
Fusion : MitelmanS100A8/MYO6 [1q21.3/6q14.1]  
Fusion PortalS100A8 1q21.3 MYO6 6q14.1 HNSC
Fusion Cancer (Beijing)S100A8 [1q21.3]  -  NAPA [19q13.32]  [FUSC003481]
Fusion : Fusion_HubAC020656.1--S100A8    ACTB--S100A8    ALDOA--S100A8    ANXA1--S100A8    ARHGAP30--S100A8    CAPZA2--S100A8    CRADD--S100A8    CRNN--S100A8    CTTN--S100A8    DDX5--S100A8    GPX3--S100A8    H1FX-AS1--S100A8    HBA1--S100A8    HBA2--S100A8    KMT2D--S100A8   
KRT13--S100A8    KRT16--S100A8    KRT4--S100A8    MPO--S100A8    PI3--S100A8    PPP6R1--S100A8    PSTPIP1--S100A8    RP11-1143G9.4--S100A8    S100A8--ANXA1    S100A8--ANXA11    S100A8--BASP1    S100A8--C5ORF58    S100A8--CCT5    S100A8--DEFA1    S100A8--DEFA1B   
S100A8--DEFA3    S100A8--FADS2    S100A8--FTL    S100A8--MYO6    S100A8--NAPA    S100A8--NFKBIA    S100A8--PLEKHH3    S100A8--PPP1R15A    S100A8--S100A8    S100A8--SNX12    S100A8--SPRR3    S100A8--SUPT16H    S100A8--TNNT1    S100A8--WDR73    S100A9--S100A8   
TALDO1--S100A8    TGM3--S100A8    TPT1--S100A8    ZFP36--S100A8   
Fusion : QuiverS100A8
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerS100A8 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)S100A8
Exome Variant ServerS100A8
GNOMAD BrowserENSG00000143546
Varsome BrowserS100A8
Genetic variants : HAPMAP6279
Genomic Variants (DGV)S100A8 [DGVbeta]
DECIPHERS100A8 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisS100A8 
ICGC Data PortalS100A8 
TCGA Data PortalS100A8 
Broad Tumor PortalS100A8
OASIS PortalS100A8 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICS100A8  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DS100A8
Mutations and Diseases : HGMDS100A8
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch S100A8
DgiDB (Drug Gene Interaction Database)S100A8
DoCM (Curated mutations)S100A8 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)S100A8 (select a term)
NCG6 (London) select S100A8
Cancer3DS100A8(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry S100A8
NextProtP05109 [Medical]
Target ValidationS100A8
Huge Navigator S100A8 [HugePedia]
snp3D : Map Gene to Disease6279
BioCentury BCIQS100A8
Clinical trials, drugs, therapy
Protein Interactions : CTD6279
Pharm GKB GenePA34910
Clinical trialS100A8
canSAR (ICR)S100A8 (select the gene name)
DataMed IndexS100A8
PubMed369 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Mon Oct 12 12:51:40 CEST 2020

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