TISIDB

Summary
Symbol	S100A8
Name	S100 calcium binding protein A8
Aliases	CGLA; CAGA; S100 calcium-binding protein A8 (calgranulin A); S100 calcium binding protein A8 (calgranulin A) ......
Chromosomal Location	1q12-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Secreted. Cytoplasm. Cytoplasm, cytoskeleton. Cell membrane; Peripheral membrane protein. Note=Predominantly localized in the cytoplasm. Upon elevation of the intracellular calcium level, translocated from the cytoplasm to the cytoskeleton and the cell membrane. Upon neutrophil activation or endothelial adhesion of monocytes, is secreted via a microtubule-mediated, alternative pathway.
Domain	PF01023 S-100/ICaBP type calcium binding domain
Function	S100A8 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. It can induce neutrophil chemotaxis and adhesion. Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions. The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase. Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transferring arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX. The extracellular functions involve proinflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its proinflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the proinflammatory cascade. Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth. Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3. Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK. Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants. Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. The iNOS-S100A8/A9 transnitrosylase complex directs selective inflammatory stimulus-dependent S-nitrosylation of GAPDH and probably multiple targets such as ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif; S100A8 seems to contribute to S-nitrosylation site selectivity.

> Gene Ontology [ TOP ]
Biological Process	GO:0001558 regulation of cell growth GO:0002237 response to molecule of bacterial origin GO:0002523 leukocyte migration involved in inflammatory response GO:0002526 acute inflammatory response GO:0002544 chronic inflammatory response GO:0002790 peptide secretion GO:0002791 regulation of peptide secretion GO:0002793 positive regulation of peptide secretion GO:0006875 cellular metal ion homeostasis GO:0006882 cellular zinc ion homeostasis GO:0006914 autophagy GO:0006919 activation of cysteine-type endopeptidase activity involved in apoptotic process GO:0007159 leukocyte cell-cell adhesion GO:0009620 response to fungus GO:0010001 glial cell differentiation GO:0010035 response to inorganic substance GO:0010038 response to metal ion GO:0010043 response to zinc ion GO:0010950 positive regulation of endopeptidase activity GO:0010952 positive regulation of peptidase activity GO:0014002 astrocyte development GO:0015833 peptide transport GO:0016049 cell growth GO:0017014 protein nitrosylation GO:0018119 peptidyl-cysteine S-nitrosylation GO:0018198 peptidyl-cysteine modification GO:0021782 glial cell development GO:0030307 positive regulation of cell growth GO:0030593 neutrophil chemotaxis GO:0030595 leukocyte chemotaxis GO:0031349 positive regulation of defense response GO:0032103 positive regulation of response to external stimulus GO:0032119 sequestering of zinc ion GO:0032496 response to lipopolysaccharide GO:0032602 chemokine production GO:0042063 gliogenesis GO:0042742 defense response to bacterium GO:0042886 amide transport GO:0043280 positive regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0043281 regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0045471 response to ethanol GO:0045862 positive regulation of proteolysis GO:0045927 positive regulation of growth GO:0046916 cellular transition metal ion homeostasis GO:0048708 astrocyte differentiation GO:0050727 regulation of inflammatory response GO:0050729 positive regulation of inflammatory response GO:0050832 defense response to fungus GO:0050900 leukocyte migration GO:0051047 positive regulation of secretion GO:0051090 regulation of sequence-specific DNA binding transcription factor activity GO:0051091 positive regulation of sequence-specific DNA binding transcription factor activity GO:0051092 positive regulation of NF-kappaB transcription factor activity GO:0051235 maintenance of location GO:0051238 sequestering of metal ion GO:0051493 regulation of cytoskeleton organization GO:0052547 regulation of peptidase activity GO:0052548 regulation of endopeptidase activity GO:0055069 zinc ion homeostasis GO:0055076 transition metal ion homeostasis GO:0060326 cell chemotaxis GO:0070486 leukocyte aggregation GO:0070488 neutrophil aggregation GO:0071621 granulocyte chemotaxis GO:0072503 cellular divalent inorganic cation homeostasis GO:0072507 divalent inorganic cation homeostasis GO:0090087 regulation of peptide transport GO:0097193 intrinsic apoptotic signaling pathway GO:0097305 response to alcohol GO:0097529 myeloid leukocyte migration GO:0097530 granulocyte migration GO:0098542 defense response to other organism GO:1990266 neutrophil migration GO:1990267 response to transition metal nanoparticle GO:2000116 regulation of cysteine-type endopeptidase activity GO:2001056 positive regulation of cysteine-type endopeptidase activity GO:2001233 regulation of apoptotic signaling pathway GO:2001235 positive regulation of apoptotic signaling pathway GO:2001242 regulation of intrinsic apoptotic signaling pathway GO:2001244 positive regulation of intrinsic apoptotic signaling pathway
Molecular Function	GO:0005504 fatty acid binding GO:0008017 microtubule binding GO:0015631 tubulin binding GO:0031406 carboxylic acid binding GO:0033293 monocarboxylic acid binding GO:0035325 Toll-like receptor binding GO:0035662 Toll-like receptor 4 binding GO:0036041 long-chain fatty acid binding GO:0043168 anion binding GO:0050542 icosanoid binding GO:0050543 icosatetraenoic acid binding GO:0050544 arachidonic acid binding GO:0050786 RAGE receptor binding
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	-
Reactome	R-HSA-6803157: Antimicrobial peptides R-HSA-168256: Immune System R-HSA-168249: Innate Immune System R-HSA-6799990: Metal sequestration by antimicrobial proteins R-HSA-6798695: Neutrophil degranulation R-HSA-5686938: Regulation of TLR by endogenous ligand R-HSA-168898: Toll-Like Receptors Cascades

Summary
Symbol	S100A8
Name	S100 calcium binding protein A8
Aliases	CGLA; CAGA; S100 calcium-binding protein A8 (calgranulin A); S100 calcium binding protein A8 (calgranulin A) ......
Chromosomal Location	1q12-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between S100A8 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between S100A8 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
27006175	Glioblastoma	Inhibit immunity (T cell function)	Elevated levels of polymorphonuclear myeloid-derived suppressor cells in patients with glioblastoma highly express S100A8/9 and arginase and suppress T cell function.
26289067	Melanoma	Inhibit immunity (T cell function)	Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at baseline and in responders, suggesting their enhanced immunosuppressive capacity. Upon the first ipilimumab infusion, nonresponders displayed elevated serum concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.
29675003	Gastric Carcinoma	Inhibit immunity	Exosomes have been shown to deliver not only various types of genetic information, mainly miRNAs, but also cytotoxin-associated gene A (CagA), a major H. pylori virulence factor.
18802069	Breast Carcinoma	Inhibit immunity	S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration.
25209187	colorectal carcinoma	Inhibit immunity	CPT11 also directly affects MDSCs by boosting secretion of proinflammatory cytokines such as TNFa, which is a key MDSC regulator, inducing their differentiation arrest via S100A8/9 and increasing their suppressive activity
23248262	Gastric Carcinoma	Inhibit immunity	S100A8/A9 has been identified as a potential target to modulate antitumor immunity by reversing MDSC-mediated immunosuppression. The ability of MDSCs to suppress T lymphocyte response and the effect of S100A8/A9 and RAGE blocking were tested in vitro by (autologous) MLR. GC patients had significantly more MDSCs than healthy individuals. These MDSCs suppressed both T lymphocyte proliferation and IFN-gamma production and had high arginase-I expression.

Summary
Symbol	S100A8
Name	S100 calcium binding protein A8
Aliases	CGLA; CAGA; S100 calcium-binding protein A8 (calgranulin A); S100 calcium binding protein A8 (calgranulin A) ......
Chromosomal Location	1q12-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of S100A8 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	S100A8
Name	S100 calcium binding protein A8
Aliases	CGLA; CAGA; S100 calcium-binding protein A8 (calgranulin A); S100 calcium binding protein A8 (calgranulin A) ......
Chromosomal Location	1q12-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of S100A8 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	0.479	0.677
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.869	0.768
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	1.488	0.46
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.033	0.969
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-1.335	0.343
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	1.77	0.332
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	-0.456	0.632
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	-0.689	0.682
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.008	0.996
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.779	0.747
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	0.436	0.906
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.522	0.16

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of S100A8 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	3.7	3.7	0.27
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	3.7	3.7	0.314
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	4.8	4.8	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	7.7	7.7	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	0	0	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	1

Summary
Symbol	S100A8
Name	S100 calcium binding protein A8
Aliases	CGLA; CAGA; S100 calcium-binding protein A8 (calgranulin A); S100 calcium binding protein A8 (calgranulin A) ......
Chromosomal Location	1q12-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of S100A8. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	S100A8
Name	S100 calcium binding protein A8
Aliases	CGLA; CAGA; S100 calcium-binding protein A8 (calgranulin A); S100 calcium binding protein A8 (calgranulin A) ......
Chromosomal Location	1q12-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of S100A8. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by S100A8. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	S100A8
Name	S100 calcium binding protein A8
Aliases	CGLA; CAGA; S100 calcium-binding protein A8 (calgranulin A); S100 calcium binding protein A8 (calgranulin A) ......
Chromosomal Location	1q12-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of S100A8. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	S100A8
Name	S100 calcium binding protein A8
Aliases	CGLA; CAGA; S100 calcium-binding protein A8 (calgranulin A); S100 calcium binding protein A8 (calgranulin A) ......
Chromosomal Location	1q12-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of S100A8 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	S100A8
Name	S100 calcium binding protein A8
Aliases	CGLA; CAGA; S100 calcium-binding protein A8 (calgranulin A); S100 calcium binding protein A8 (calgranulin A) ......
Chromosomal Location	1q12-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between S100A8 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	S100A8
Name	S100 calcium binding protein A8
Aliases	CGLA; CAGA; S100 calcium-binding protein A8 (calgranulin A); S100 calcium binding protein A8 (calgranulin A) ......
Chromosomal Location	1q12-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting S100A8 collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting S100A8.

ID	Name	Drug Type	Targets	#Targets
DB01373	Calcium	Small Molecule	ALPP, AOC1, ATP2C1, BMP4, CACNA1C, CAST, COMP, CP, MGP, PCDH19, PD ......	19
DB01593	Zinc	Small Molecule	A1BG, A2M, AGT, AHSG, ALDOA, APCS, APLP1, APLP2, APOA1, APOA2, APO ......	119
DB09130	Copper	Small Molecule	A1BG, ACTG1, ACTN1, ACY1, AFM, AGT, AHCY, AHSG, AKR1A1, ANXA4, ANX ......	141

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