VTCN1 (V-set domain containing T cell activation inhibitor 1)

2008-02-01   Panduka Samarawardana , Kenneth R Shroyer 

Department of Pathology, University of Colorado at Denver, Health Sciences Center, (PS); Department of Pathology, Stony Brook University Medical Center, Aurora, CO 80045, USA (KRS)

Identity

HGNC
LOCATION
1p13.1
LOCUSID
ALIAS
B7-H4,B7H4,B7S1,B7X,B7h.5,PRO1291,VCTN1
FUSION GENES

DNA/RNA

Description

The VTCN1 (B7-H4) gene located in chromosome 1p13.1, consists of six exons and five introns and the coding region spans 849 bp. The mature protein is coded by the exons 3, 4, and part 5 while exons 1 and 2 encodes a signal peptide. The IgV-IgC domain, comprised of the extracellular region, is coded by exons 3, 4 and parts of 5 (Chen L. et al. 2003).

Transcription

B7-H4 mRNA can be detected in many tissues including placenta, kidney, liver, lung, ovary, testis and spleen. There are two transcripts of B7-H4 and both transcripts share complete homology with exons 1 to 5 in the full length B7-H4 gene. The smaller transcript of the two, generated by alternative splicing, lacks part of exon 6 (Chen L. et al. 2003).

Pseudogene

A possible B7-H4 pseudogene has a single exon with 94% similar nucleotide sequence identity to the cDNA of B-7H4 and is located in chromosome 20p11.1 (Chen L. et al. 2003).

Proteins

Description

The predicted 282-amino acid B7-H4 protein contains a 2-amino acid intracellular domain, a large hydrophobic type 1 transmembrane domain and an extracellular domain (Prasad et al. 2003).

Expression

Prasad et al. (2003) showed that B7-H4 is expressed in professional antigen presenting cells. Although B7-H4 is overexpressed in several human cancers including ovary, endometrium, lung and kidney, its expression is limited in normal tissues. Shroyer et al. (2005) showed that there is a limited focal expression of B7-H4 by immunohistochemistry in several normal human tissues including fallopian tubes, endometrial glands, pancreas, larynx, lung, kidney and urinary bladder.

Localisation

B7-H4 is localized to the cell surface and cytoplasm of epithelial cells and macrophages. Expression in benign glandular cells (ductal epithelium in breast and pancreas) is localized to the apical cell surface but there is circumferential membranous localization in B7-H4 positive tumor cells.

Function

Published data shows that B7-H4 functions as a negative regulator of T cell responses and it negatively regulates the T cell immunity by the inhibition of T cell proliferation, cytokine production and cell cycle progression. Prasad et al. (2003) reported that B7S1/B7-H4 is expressed on professional antigen presenting cells, binds to its putative receptor on activated T cells, and inhibits T cell activation and IL2 production. Sica G.L..et al (2003) also reported that B7-H4 inhibits T cell activation and the production of both IL2 and IL10. They further showed that B7-H4 inhibits the induction of Cytolytic T Lymphocytes (CTL) in vitro and it also arrests cell cycle of T cells in G0/G1 phase.
B7-H4 may also play a role in tumor biology by providing tumors with a protective mechanism to escape from immune surveillance. Several human cancers such ovary, endometrium, breast, kidney and lung (non small cell) are known to overexpress B-7H4 and the level of B7-H4 expression in these tumors has been correlated to the number of tumor-associated and tumor-infiltrating T cells. Papkoff J. et al. (2005) found that overexpressed B7-H4 promotes epithelial cell transformation by protecting cells from apoptosis and a siRNA knockout of B7-H4 in tumor cell lines lead to an increased apoptosis. Kryczek et al. (2006) reported that primary ovarian tumor cells express exclusively intracellular B7-H4 protein, whereas the majority of ovarian tumor macrophages, but not tumor T cells or blood macrophages, express surface B7-H4, possibly by stimulation with tumor-associated IL6 and IL10. They also showed that B7-H4 expressing tumor macrophages suppressed HER2 specific T-cell proliferation and cytotoxicity. Further, the blocking of B7-H4 expression with specific oligonucleotides improved the tumor-associated antigen T-cell responses. They concluded that B7-H4 expressing tumor macrophages are a suppressive cell population in ovarian cancer and might prove to be a good therapeutic target.

Homology

B7-H4 shares a 24%-31% homology with other members of the B7 family and has the highest homology with B7H3 with 31% homology (Chen L. et al. 2003).

Implicated in

Entity name
Ovarian Cancer
Note
Chen L et al.(2003) first reported the detection of B7-H4 expression in ovarian cancer but not in normal ovarian tissue. Papkoff et al. (2005) showed that B7-H4 mRNA and protein are overexpressed in human serous ovarian cancers and breast cancers with relatively little or no expression in normal tissues. Also they described that overexpression of B7-H4 in a human ovarian cancer cell line with little endogenous B7-H4 expression, increased the tumor formation in SCID mice. Shroyer et al. (2006) found that B7-H4 is highly over-expressed in primary and metastatic serous, endometrioid, and clear cell carcinomas. In contrast, B7-H4 is not expressed in most mucinous ovarian cancers. Kryczek I et al (2006) published that primary ovarian tumor cells express intracellular B7-H4, whereas a fraction of tumor macrophages expressed surface B7-H4. These authors concluded that B7-H4 expression in tumor macrophages, rather than in the ovarian tumor cells, was relevant with regard to the suppression of tumor-associated antigen-specific T cell immunity. Kim NW et al (2006) showed that elevated levels of B7-H4 can be found in the serum of patients with ovarian cancer and could play a role as a biomarker in ovarian cancer. They also developed a method based on ELISA to detect B7-H4 in the serum. Diamandis E.P. (2007) reported B7-H4 expression was low in normal ovaries and in benign tumors while half of early stage and two-thirds of late stage cancers over-expressed B7-H4.
Entity name
Uterine Endometrial Cancer
Note
Shroyer K. et al (2007) showed that the proportion and intensity of B7-H4 staining were increased in the progression from normal, hyperplastic and malignant endometrial glandular mucosa. The proportion of B7-H4 positive tumor cells and staining intensity was also higher in high risk tumors than in low risk tumors. The proportion of B7-H4 positive tumor cells was inversely related to the number of CD3-positive and CD8-positive tumor-associated lymphocytes.
Entity name
Breast Cancer
Note
Shroyer et al. (2005) showed that B7-H4 is consistently over-expressed in primary and metastatic ductal and lobular breast cancers and its expression is correlated with a negative progesterone receptor status, negative Her-2/neu status and with a history of neo-adjuvant chemotherapy. There was also a significant association between a high proportion of B7-H4 positive cells in invasive ductal carcinomas and decreased number of tumor infiltrating lymphocytes. B7-H4 immunohistochemical expression was independent of tumor grade, stage or the size of the tumors.
Entity name
Non Small Cell Lung Cancer
Note
Wang X. et al (2006) showed that B7-H4 is overexpressed in Non Small Cell Lung Cancer and its overexpression is negatively correlated with tumor infiltrating lymphocytes and positively associated with lymph node metastasis.
Entity name
Renal Cell Cancer (RCC)
Note
Kwon E.D. et al (2006) reported that B7-H4 was overexpressed in 59% of 259 RCC tumor specimens analyzed and that tumor cell B7-H4 expression was associated with adverse clinical and pathologic features, including constitutional symptoms, tumor necrosis, and advanced tumor size, stage, and grade. Also B7-H4 expression when coupled with B7S1 expression was associated with a poor survival from RCC. Additionally, they noted that tumor vasculature was significantly positive for endothelial B7-H4 expression, compared with the normal adjacent renal tissue vessels.
Entity name
Prostate Cancer
Note
Allison J.P. et al (2007) published that B7x/B7-H4 is overexpressed in human prostate cancer and patients with stronger immunohistochemical B7-H4 expression had higher rates of clinical cancer recurrences and cancer specific deaths.

Bibliography

Pubmed IDLast YearTitleAuthors
167251842006Differential gene expression profiles between tumor biopsies and short-term primary cultures of ovarian serous carcinomas: identification of novel molecular biomarkers for early diagnosis and therapy.Bignotti E et al
145689392003Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family.Choi IH et al
159608132005The B7 family of immune-regulatory ligands.Collins M et al
174143162007The new B7s: playing a pivotal role in tumor immunity.Flies DB et al
167988832006B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival.Krambeck AE et al
178757322007Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma.Kryczek I et al
166066662006B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma.Kryczek I et al
175096742007B7-H4 (DD-O110) is overexpressed in high risk uterine endometrioid adenocarcinomas and inversely correlated with tumor T-cell infiltration.Miyatake T et al
180913772007B7-h4 expression in a range of breast pathology: correlation with tumor T-cell infiltration.Mugler KC et al
128181662003B7S1, a novel B7 family member that negatively regulates T cell activation.Prasad DV et al
158783392005The immunomodulatory protein B7-H4 is overexpressed in breast and ovarian cancers and promotes epithelial cell transformation.Salceda S et al
128181652003B7-H4, a molecule of the B7 family, negatively regulates T cell immunity.Sica GL et al
174987842007B7-H4 is over-expressed in early-stage ovarian cancer and is independent of CA125 expression.Simon I et al
174907322007Evaluation of the novel serum markers B7-H4, Spondin 2, and DcR3 for diagnosis and early detection of ovarian cancer.Simon I et al
164522142006B7-h4 is a novel membrane-bound protein and a candidate serum and tissue biomarker for ovarian cancer.Simon I et al
167822262006B7-H3 and B7-H4 expression in non-small-cell lung cancer.Sun Y et al
162561782006B7-H4 overexpression in ovarian tumors.Tringler B et al
180427032007B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome.Zang X et al

Other Information

Locus ID:

NCBI: 79679
MIM: 608162
HGNC: 28873
Ensembl: ENSG00000134258

Variants:

dbSNP: 79679
ClinVar: 79679
TCGA: ENSG00000134258
COSMIC: VTCN1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000134258ENST00000328189Q7Z7D3
ENSG00000134258ENST00000359008Q5T2L0
ENSG00000134258ENST00000369458Q7Z7D3
ENSG00000134258ENST00000430871A0A087X1M4
ENSG00000134258ENST00000539893Q7Z7D3

Expression (GTEx)

0
5
10
15
20
25
30

Pathways

PathwaySourceExternal ID
Cell adhesion molecules (CAMs)KEGGko04514
Cell adhesion molecules (CAMs)KEGGhsa04514

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
166066662006B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma.223
128181652003B7-H4, a molecule of the B7 family, negatively regulates T cell immunity.194
128181662003B7S1, a novel B7 family member that negatively regulates T cell activation.132
167988832006B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival.98
167854962006Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells.74
145689392003Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family.71
158783392005The immunomodulatory protein B7-H4 is overexpressed in breast and ovarian cancers and promotes epithelial cell transformation.57
215198292011B7-H4 expression associates with cancer progression and predicts patient's survival in human esophageal squamous cell carcinoma.49
237225402013Novel recombinant human b7-h4 antibodies overcome tumoral immune escape to potentiate T-cell antitumor responses.40
274402662017Differential Expression and Significance of PD-L1, IDO-1, and B7-H4 in Human Lung Cancer.38

Citation

Panduka Samarawardana ; Kenneth R Shroyer

VTCN1 (V-set domain containing T cell activation inhibitor 1)

Atlas Genet Cytogenet Oncol Haematol. 2008-02-01

Online version: http://atlasgeneticsoncology.org/gene/44144/vtcn1