| Written | 2008-02 | 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 |
| Alias_symbol (synonym) | B7-H4 |
| FLJ22418 | |
| B7S1 | |
| B7X | |
| B7H4 | |
| Other alias | B7h.5 |
| PRO1291 | |
| RP11-229A19.4 | |
| HGNC (Hugo) | VTCN1 |
| LocusID (NCBI) | 79679 |
| Atlas_Id | 44144 |
| Location | 1p13.1 [Link to chromosome band 1p13] |
| Location_base_pair | Starts at 117143587 and ends at 117203836 bp from pter ( according to hg19-Feb_2009) [Mapping VTCN1.png] |
| Fusion genes (updated 2016) | VTCN1 (1p13.1) / NUP88 (17p13.2) | VTCN1 (1p13.1) / PTGFRN (1p13.1) |
| 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). |
| Protein |
| 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 |
| Note | |
| Entity | 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 | 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 | 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 | 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 | 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 | 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 |
| Differential 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, Tassi RA, Calza S, Ravaggi A, Romani C, Rossi E, Falchetti M, Odicino FE, Pecorelli S, Santin AD |
| Gynecologic oncology. 2006 ; 103 (2) : 405-416. |
| PMID 16725184 |
| Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family. |
| Choi IH, Zhu G, Sica GL, Strome SE, Cheville JC, Lau JS, Zhu Y, Flies DB, Tamada K, Chen L |
| Journal of immunology (Baltimore, Md. : 1950). 2003 ; 171 (9) : 4650-4654. |
| PMID 14568939 |
| The B7 family of immune-regulatory ligands. |
| Collins M, Ling V, Carreno BM |
| Genome biology. 2005 ; 6 (6) : page 223. |
| PMID 15960813 |
| The new B7s: playing a pivotal role in tumor immunity. |
| Flies DB, Chen L |
| Journal of immunotherapy (Hagerstown, Md. : 1997). 2007 ; 30 (3) : 251-260. |
| PMID 17414316 |
| B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival. |
| Krambeck AE, Thompson RH, Dong H, Lohse CM, Park ES, Kuntz SM, Leibovich BC, Blute ML, Cheville JC, Kwon ED |
| Proceedings of the National Academy of Sciences of the United States of America. 2006 ; 103 (27) : 10391-10396. |
| PMID 16798883 |
| Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. |
| Kryczek I, Wei S, Zhu G, Myers L, Mottram P, Cheng P, Chen L, Coukos G, Zou W |
| Cancer research. 2007 ; 67 (18) : 8900-8905. |
| PMID 17875732 |
| B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. |
| Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P, Brumlik M, Cheng P, Curiel T, Myers L, Lackner A, Alvarez X, Ochoa A, Chen L, Zou W |
| The Journal of experimental medicine. 2006 ; 203 (4) : 871-881. |
| PMID 16606666 |
| B7-H4 (DD-O110) is overexpressed in high risk uterine endometrioid adenocarcinomas and inversely correlated with tumor T-cell infiltration. |
| Miyatake T, Tringler B, Liu W, Liu SH, Papkoff J, Enomoto T, Torkko KC, Dehn DL, Swisher A, Shroyer KR |
| Gynecologic oncology. 2007 ; 106 (1) : 119-127. |
| PMID 17509674 |
| B7-h4 expression in a range of breast pathology: correlation with tumor T-cell infiltration. |
| Mugler KC, Singh M, Tringler B, Torkko KC, Liu W, Papkoff J, Shroyer KR |
| Applied immunohistochemistry & molecular morphology : AIMM / official publication of the Society for Applied Immunohistochemistry. 2007 ; 15 (4) : 363-370. |
| PMID 18091377 |
| B7S1, a novel B7 family member that negatively regulates T cell activation. |
| Prasad DV, Richards S, Mai XM, Dong C |
| Immunity. 2003 ; 18 (6) : 863-873. |
| PMID 12818166 |
| The immunomodulatory protein B7-H4 is overexpressed in breast and ovarian cancers and promotes epithelial cell transformation. |
| Salceda S, Tang T, Kmet M, Munteanu A, Ghosh M, Macina R, Liu W, Pilkington G, Papkoff J |
| Experimental cell research. 2005 ; 306 (1) : 128-141. |
| PMID 15878339 |
| B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. |
| Sica GL, Choi IH, Zhu G, Tamada K, Wang SD, Tamura H, Chapoval AI, Flies DB, Bajorath J, Chen L |
| Immunity. 2003 ; 18 (6) : 849-861. |
| PMID 12818165 |
| B7-H4 is over-expressed in early-stage ovarian cancer and is independent of CA125 expression. |
| Simon I, Katsaros D, Rigault de la Longrais I, Massobrio M, Scorilas A, Kim NW, Sarno MJ, Wolfert RL, Diamandis EP |
| Gynecologic oncology. 2007 ; 106 (2) : 334-341. |
| PMID 17498784 |
| Evaluation of the novel serum markers B7-H4, Spondin 2, and DcR3 for diagnosis and early detection of ovarian cancer. |
| Simon I, Liu Y, Krall KL, Urban N, Wolfert RL, Kim NW, McIntosh MW |
| Gynecologic oncology. 2007 ; 106 (1) : 112-118. |
| PMID 17490732 |
| B7-h4 is a novel membrane-bound protein and a candidate serum and tissue biomarker for ovarian cancer. |
| Simon I, Zhuo S, Corral L, Diamandis EP, Sarno MJ, Wolfert RL, Kim NW |
| Cancer research. 2006 ; 66 (3) : 1570-1575. |
| PMID 16452214 |
| B7-H3 and B7-H4 expression in non-small-cell lung cancer. |
| Sun Y, Wang Y, Zhao J, Gu M, Giscombe R, Lefvert AK, Wang X |
| Lung cancer (Amsterdam, Netherlands). 2006 ; 53 (2) : 143-151. |
| PMID 16782226 |
| B7-H4 overexpression in ovarian tumors. |
| Tringler B, Liu W, Corral L, Torkko KC, Enomoto T, Davidson S, Lucia MS, Heinz DE, Papkoff J, Shroyer KR |
| Gynecologic oncology. 2006 ; 100 (1) : 44-52. |
| PMID 16256178 |
| B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome. |
| Zang X, Thompson RH, Al-Ahmadie HA, Serio AM, Reuter VE, Eastham JA, Scardino PT, Sharma P, Allison JP |
| Proceedings of the National Academy of Sciences of the United States of America. 2007 ; 104 (49) : 19458-19463. |
| PMID 18042703 |
| Citation |
| This paper should be referenced as such : |
| Samarawardana, P ; Shroyer, KR |
| VTCN1 (V-set domain containing T cell activation inhibitor 1) |
| Atlas Genet Cytogenet Oncol Haematol. 2008;12(6):452-454. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/VTCN1ID44144ch1p13.html |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Fri Jun 30 11:21:17 CEST 2017 |
For comments and suggestions or contributions, please contact us