TISIDB

Summary
Symbol	HSPA4
Name	heat shock 70kDa protein 4
Aliases	HS24/P52; HSPH2; hsp70 RY; heat shock 70kD protein 4; APG-2; HEL-S-5a; RY; hsp70; hsp70RY; epididymis secret ......
Chromosomal Location	5q31.1
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	Cytoplasm
Domain	PF00012 Hsp70 protein
Function	-

> Gene Ontology [ TOP ]
Biological Process	GO:0006626 protein targeting to mitochondrion GO:0006839 mitochondrial transport GO:0006986 response to unfolded protein GO:0007006 mitochondrial membrane organization GO:0007008 outer mitochondrial membrane organization GO:0017038 protein import GO:0035966 response to topologically incorrect protein GO:0044743 intracellular protein transmembrane import GO:0045040 protein import into mitochondrial outer membrane GO:0051131 chaperone-mediated protein complex assembly GO:0065002 intracellular protein transmembrane transport GO:0070585 protein localization to mitochondrion GO:0071806 protein transmembrane transport GO:0072655 establishment of protein localization to mitochondrion GO:0072657 protein localization to membrane GO:0090150 establishment of protein localization to membrane GO:0090151 establishment of protein localization to mitochondrial membrane GO:1990542 mitochondrial transmembrane transport
Molecular Function	-
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04530 Tight junction hsa04612 Antigen processing and presentation
Reactome	R-HSA-3371556: Cellular response to heat stress R-HSA-2262752: Cellular responses to stress R-HSA-3371453: Regulation of HSF1-mediated heat shock response

Summary
Symbol	HSPA4
Name	heat shock 70kDa protein 4
Aliases	HS24/P52; HSPH2; hsp70 RY; heat shock 70kD protein 4; APG-2; HEL-S-5a; RY; hsp70; hsp70RY; epididymis secret ......
Chromosomal Location	5q31.1
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between HSPA4 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 HSPA4 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
26598503	Breast Carcinoma; Lung Carcinoma; Ovarian Carcinoma	Inhibit immunity (T cell function)	Exosomes, via heat shock protein 70 (HSP70) expressed in their membrane, are able to interact with the toll-like receptor 2 (TLR2) on myeloid-derived suppressive cells (MDSCs), thereby activating them.
16425224	Melanoma	Promote immunity (T/NK cell function); essential for immunotherapy	HSP70 vaccine in combination with gene therapy with plasmid DNA encoding sPD-1 overcomes immune resistance and suppresses the progression of pulmonary metastatic melanoma.
22396543	Hepatocellular Carcinoma	Promote immunity (NK cell function)	ELISA results showed that the production of HSP60, HSP70, and HSP90 was up-regulated in both cell lines in a stress-specific manner. Acting as a decoy, the HSP-bearing exosomes efficiently stimulated NK cell cytotoxicity and granzyme B production, up-regulated the expression of inhibitory receptor CD94, and down-regulated the expression of activating receptors CD69, NKG2D, and NKp44.
18089828	Prostate Carcinoma	Promote immunity (T cell function); essential for immunotherapy	Induction of hsp70-mediated Th17 autoimmunity can be exploited as immunotherapy for metastatic prostate cancer. We show here that, in the prostate, hsp70 induces interleukin (IL)-6, which triggers a CD4- and CD8-dependent progressive autoimmune reactivity, associated with IL-17 expression.
29478948	Melanoma	Inhibit immunity (T cell function)	Targeting HSP70/90 in melanoma cells resulted in reduced induction of immune suppressive cells on a phenotypic and functional basis, for which a more potent effect was observed when HSP90 was inhibited under hypoxic conditions.
16140966	Colon Carcinoma	Promote immunity	Hsp70 induces DC maturation and phagocytosis of cellular debris both in vitro and in vivo, which are conducive to CTL response to chaperoned and nonchaperoned antigens.

Summary
Symbol	HSPA4
Name	heat shock 70kDa protein 4
Aliases	HS24/P52; HSPH2; hsp70 RY; heat shock 70kD protein 4; APG-2; HEL-S-5a; RY; hsp70; hsp70RY; epididymis secret ......
Chromosomal Location	5q31.1
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 HSPA4 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	HSPA4
Name	heat shock 70kDa protein 4
Aliases	HS24/P52; HSPH2; hsp70 RY; heat shock 70kD protein 4; APG-2; HEL-S-5a; RY; hsp70; hsp70RY; epididymis secret ......
Chromosomal Location	5q31.1
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 HSPA4 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	0.091	0.676
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.408	0.865
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.144	0.937
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.236	0.355
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.241	0.914
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.231	0.934
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.119	0.799
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	-0.012	0.996
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.289	0.9
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.059	0.971
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	0.1	0.967
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.027	0.669

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of HSPA4 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	7.1	0	7.1	0.452
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	10	0	10	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	3.7	1.4	2.3	0.469
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	3.7	1.7	2	0.532
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	0	0	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	0	0	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	2.6	0	2.6	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	4.5	0	4.5	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	HSPA4
Name	heat shock 70kDa protein 4
Aliases	HS24/P52; HSPH2; hsp70 RY; heat shock 70kD protein 4; APG-2; HEL-S-5a; RY; hsp70; hsp70RY; epididymis secret ......
Chromosomal Location	5q31.1
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of HSPA4. 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	HSPA4
Name	heat shock 70kDa protein 4
Aliases	HS24/P52; HSPH2; hsp70 RY; heat shock 70kD protein 4; APG-2; HEL-S-5a; RY; hsp70; hsp70RY; epididymis secret ......
Chromosomal Location	5q31.1
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of HSPA4. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by HSPA4. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	HSPA4
Name	heat shock 70kDa protein 4
Aliases	HS24/P52; HSPH2; hsp70 RY; heat shock 70kD protein 4; APG-2; HEL-S-5a; RY; hsp70; hsp70RY; epididymis secret ......
Chromosomal Location	5q31.1
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of HSPA4. 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	HSPA4
Name	heat shock 70kDa protein 4
Aliases	HS24/P52; HSPH2; hsp70 RY; heat shock 70kD protein 4; APG-2; HEL-S-5a; RY; hsp70; hsp70RY; epididymis secret ......
Chromosomal Location	5q31.1
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of HSPA4 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	HSPA4
Name	heat shock 70kDa protein 4
Aliases	HS24/P52; HSPH2; hsp70 RY; heat shock 70kD protein 4; APG-2; HEL-S-5a; RY; hsp70; hsp70RY; epididymis secret ......
Chromosomal Location	5q31.1
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between HSPA4 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	HSPA4
Name	heat shock 70kDa protein 4
Aliases	HS24/P52; HSPH2; hsp70 RY; heat shock 70kD protein 4; APG-2; HEL-S-5a; RY; hsp70; hsp70RY; epididymis secret ......
Chromosomal Location	5q31.1
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting HSPA4 collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting HSPA4.

ID	Name	Drug Type	Targets	#Targets
DB12695	Phenethyl Isothiocyanate	Small Molecule	ACTA2, ACTB, ATP5B, ATP5I, ATP5L, CYB5B, DIABLO, FBXO41, HNRNPF, H ......	45

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