Gene Summary

Gene:TAP1; transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)
Aliases: APT1, PSF1, ABC17, ABCB2, PSF-1, RING4, TAP1N, D6S114E, TAP1*0102N
Summary:The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is involved in the pumping of degraded cytosolic peptides across the endoplasmic reticulum into the membrane-bound compartment where class I molecules assemble. Mutations in this gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:antigen peptide transporter 1
Source:NCBIAccessed: 11 August, 2015


What does this gene/protein do?
Show (32)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 11 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Antineoplastic Agents
  • Alleles
  • Polymerase Chain Reaction
  • ATP-Binding Cassette Transporters
  • Multienzyme Complexes
  • Cancer Gene Expression Regulation
  • HLA Antigens
  • Tumor Antigens
  • Major Histocompatibility Complex
  • Genetic Predisposition
  • Mutation
  • Down-Regulation
  • Transfection
  • Up-Regulation
  • Proteasome Endopeptidase Complex
  • Colorectal Cancer
  • Tumor Escape
  • Viral Matrix Proteins
  • Single Nucleotide Polymorphism
  • Chromosome 6
  • T-Lymphocytes, Cytotoxic
  • Transcription
  • Interferon-gamma
  • Messenger RNA
  • Uterine Cancer
  • Histocompatibility Antigens Class I
  • Melanoma
  • Trans-Activators
  • Genotype
  • Gene Expression
  • Base Sequence
  • Squamous Cell Carcinoma
  • Cysteine Endopeptidases
  • Genes, MHC Class I
  • Case-Control Studies
  • Molecular Sequence Data
  • Antigen Presentation
  • Promoter Regions
  • Immunohistochemistry
Tag cloud generated 11 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TAP1 (cancer-related)

Mehta AM, Spaans VM, Mahendra NB, et al.
Differences in genetic variation in antigen-processing machinery components and association with cervical carcinoma risk in two Indonesian populations.
Immunogenetics. 2015; 67(5-6):267-75 [PubMed] Free Access to Full Article Related Publications
Genetic variation of antigen-processing machinery (APM) components has been shown to be associated with cervical carcinoma risk and outcome in a genetically homogeneous Dutch population. However, the role of APM component single nucleotide polymorphisms (SNPs) in genetically heterogeneous populations with different distributions of human papillomavirus (HPV) subtypes remains unclear. Eleven non-synonymous, coding SNPs in the TAP1, TAP2, LMP2, LMP7 and ERAP1 genes were genotyped in cervical carcinoma patients and healthy controls from two distinct Indonesian populations (Balinese and Javanese). Individual genotype and allele distributions were investigated using single-marker analysis, and combined SNP effects were assessed by haplotype construction and haplotype interaction analysis. Allele distribution patterns in Bali and Java differed in relation to cervical carcinoma risk, with four ERAP1 SNPs and one TAP2 SNP in the Javanese population showing significant association with cervical carcinoma risk, while in the Balinese population, only one TAP2 SNP showed this association. Multimarker analysis demonstrated that in the Javanese patients, one specific haplotype, consisting of the ERAP1-575 locus on chromosome 5 and the TAP2-379 and TAP2-651 loci on chromosome 6, was significantly associated with cervical carcinoma risk (global P = 0.008); no significant haplotype associations were found in the Balinese population. These data indicate not only that genetic variation in APM component genes is associated with cervical carcinoma risk in Indonesia but also that the patterns of association differ depending on background genetic composition and possibly on differences in HPV type distribution.

Zhan HQ, Chen H, Wang CF, Zhu XZ
A case of PSF-TFE3 gene fusion in Xp11.2 renal cell carcinoma with melanotic features.
Hum Pathol. 2015; 46(3):476-81 [PubMed] Related Publications
Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) with PSF-TFE3 gene fusion is a rare neoplasm. Only 22 cases of Xp11.2 RCCs with PSF-TFE3 have been reported to date. We describe an additional case of Xp11.2 RCC with PSF-TFE3 showing melanotic features. Microscopically, the histologic features mimic clear cell renal cell carcinoma. However, the dark-brown pigments were identified and could be demonstrated as melanins. Immunohistochemically, the tumor cells were widely positive for CD10, human melanoma black 45, and TFE3 but negative for cytokeratins, vimentin, Melan-A, microphthalmia-associated transcription factor, smooth muscle actin, and S-100 protein. Genetically, we demonstrated PSF-TFE3 fusion between exon 9 of PSF and exon 5 of TFE3. The patient was free of disease with 50 months of follow-up. The prognosis of this type of tumor requires more cases because of limited number of cases and follow-up period. Xp11.2 RCC with PSF-TFE3 inevitably requires differentiation from other kidney neoplasms. Immunohistochemical and molecular genetic analyses are essential for accurate diagnosis.

Zhang J, Wu Q, Wang Z, et al.
Knockdown of PSF1 expression inhibits cell proliferation in lung cancer cells in vitro.
Tumour Biol. 2015; 36(3):2163-8 [PubMed] Related Publications
Partner of sld five 1 (PSF1) is a member of the heterotetrameric complex termed GINS. Previous studies have shown that PSF1 is unregulated in several cancer and associated with tumor malignant characters. However, the effects of PSF1 in lung cancer are still unclear. The goal of this study was to investigate the effects of PSF1 on the proliferation capacities of lung cancer. To start with, expression of PSF1 in 22 human lung cancer samples and adjacent non-tumor samples were detected by real-time RT-PCR and Western blotting. Our results showed that PSF1 was overexpressed in lung cancer samples compared to adjacent non-tumor samples. To achieve better insights of PSF1 functions in lung cancer cells, we used PSF1-specific small interfering RNA (siRNA) successfully inhibit the expression of PSF1 in messenger RNA (mRNA) and protein levels. In addition, we used lung cancer cell lines with different p53 gene background (p53 null and p53 wild-type). The results showed that knockdown of PSF1 inhibited cell proliferation and caused cell cycle arrest of lung cancer cells in a p53-independent manner. Our data indicated that PSF1 is functionally involved in lung cancer cell proliferation and is a potential target for lung cancer therapy.

Aissani B, Boehme AK, Wiener HW, et al.
SNP screening of central MHC-identified HLA-DMB as a candidate susceptibility gene for HIV-related Kaposi's sarcoma.
Genes Immun. 2014; 15(6):424-9 [PubMed] Free Access to Full Article Related Publications
The major histocompatibility complex (MHC) region on chromosome 6p21.3 is suspected to host susceptibility loci for HIV-related Kaposi's sarcoma (HIV-KS). A nested case-control study in the Multicenter AIDS Cohort Study was designed to conduct fine genetic association mapping across central MHC. Individuals co-infected with HIV-1 and human herpes virus-8 who later developed KS were defined as cases (n=354) and were matched 1:1 with co-infected KS-free controls. We report data for new independent MHC class II and III susceptibility loci. In particular, class II HLA-DMB emerged as a strong candidate, with the intronic variant rs6902982 A>G associated with a fourfold increase of risk (odds ratio (OR)=4.09; 95% confidence interval (CI)=1.90-8.80; P=0.0003). A striking multiplicative effect on the estimated risk was associated with further carriage of two non-synonymous variants, rs1800453 A>G (Asp697Gly) and rs4148880 A>G (Ile393Val), in the linked TAP1 gene (OR=10.5; 95% CI=2.54-43.6; P=0.0012). The class III susceptibility variant is moderately associated with HIV-KS and lies within a 120-kb-long haplotype (OR=1.52; 95% CI=1.01-2.28; P=0.047) formed by rs7029 A>G (GPANK1 3' untranslated region), rs1065356 G>A (LY6G6C), rs3749953 A>G (MSH5-SAPCD1 read through) and rs707926 G>A (VARS). Our data suggest that antigen processing by MHC class II molecules is a target pathway in the pathogenesis of HIV-KS.

Yamauchi T, Takeuchi S, Maehara N, Kuroda Y
The genotype of the transporter associated with antigen processing gene affects susceptibility to colorectal cancer in Japanese.
Environ Health Prev Med. 2014; 19(4):265-70 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Although colorectal cancer (CRC) is one of the most frequent malignancies in Japan, the associated genetic factors remain to be elucidated. Functional loss of the transporter associated with antigen processing (TAP) 1 gene induces carcinogenesis. We investigated whether single nucleotide polymorphisms (SNPs) in the TAP1 gene (rs735883) are associated with susceptibility to CRC in a Japanese population.
METHODS: The study participants were 143 cases and 243 clinical controls. After extracting DNA from their peripheral blood cells, genotyping was conducted by the polymerase chain reaction-restriction fragment length polymorphism method.
RESULTS: Participants with a mutated allele had an increased risk for CRC. The adjusted odds ratios for the C/T, T/T, and the mutation type (C/T + T/T) compared to that of wild type (C/C) were 2.27 [95 % confidence interval (CI), 1.43-3.67], 1.95 (95 % CI, 0.88-4.30), and 2.22 (95 % CI, 1.42-3.55), respectively. Furthermore, a significant trend in the rate of cases was observed with an increasing number of mutated alleles (P for trend = 0.0068).
CONCLUSIONS: The genotype of the TAP1 gene is associated with susceptibility to CRC.

Wang C, Cicek MS, Charbonneau B, et al.
Tumor hypomethylation at 6p21.3 associates with longer time to recurrence of high-grade serous epithelial ovarian cancer.
Cancer Res. 2014; 74(11):3084-91 [PubMed] Free Access to Full Article Related Publications
To reveal biologic mechanisms underlying clinical outcome of high-grade serous (HGS) epithelial ovarian carcinomas (EOC), we evaluated the association between tumor epigenetic changes and time to recurrence (TTR). We assessed methylation at approximately 450,000 genome-wide CpGs in tumors of 337 Mayo Clinic (Rochester, MN) patients. Semi-supervised clustering of discovery (n=168) and validation (n=169) sets was used to determine clinically relevant methylation classes. Clustering identified two methylation classes based on 60 informative CpGs, which differed in TTR in the validation set [R vs. L class, P=2.9×10(-3), HR=0.52; 95% confidence interval (CI), 0.34-0.80]. Follow-up analyses considered genome-wide tumor mRNA expression (n=104) and CD8 T-cell infiltration (n=89) in patient subsets. Hypomethylation of CpGs located in 6p21.3 in the R class associated with cis upregulation of genes enriched in immune response processes (TAP1, PSMB8, PSMB9, HLA-DQB1, HLA-DQB2, HLA-DMA, and HLA-DOA), increased CD8 T-cell tumor infiltration (P=7.6×10(-5)), and trans-regulation of genes in immune-related pathways (P=1.6×10(-32)). This is the most comprehensive assessment of clinical outcomes with regard to epithelial ovarian carcinoma tumor methylation to date. Collectively, these results suggest that an epigenetically mediated immune response is a predictor of recurrence and, possibly, treatment response for HGS EOC.

Natter C, Polterauer S, Rahhal-Schupp J, et al.
Association of TAP gene polymorphisms and risk of cervical intraepithelial neoplasia.
Dis Markers. 2013; 35(2):79-84 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Transporter associated with antigen processing (TAP) is responsible for peptide loading onto class I major histocompatibility complex (MHC-I) molecules. TAP seems to facilitate the detection of HPV by MHC-I molecules and contributes to successful eradication of HPV. TAP polymorphisms could have an important impact on the course of HPV infection.
OBJECTIVE: The aim of this study is to evaluate the association between five TAP gene polymorphisms and the risk of CIN. Methods. This case-control study investigated five common TAP polymorphisms in TAP1 (1341 and 2254) and TAP2 (1135, 1693, and 1993) in 616 women with CIN and 206 controls. Associations between gene polymorphisms and risk of CIN were analysed by univariate and multivariable models. The combined effect of the five TAP gene polymorphisms on the risk for CIN was investigated by haplotype analysis.
RESULTS: No significant difference in genotype distribution of the five TAP polymorphisms was observed in women with CIN and controls. Haplotype analysis revealed that women with haplotype mut-wt-wt-wt-wt (TAP polymorphisms t1135-t1341-t1693-t1993-t2254) had a significantly lower risk for CIN, compared to women with the haplotype wt-wt-wt-wt-wt (P = 0.006; OR 0.5 [0.35-0.84]).
CONCLUSION: Identification of this haplotype combination could be used to identify women, less susceptible for development of CIN following HPV infection.

Ozbas-Gerceker F, Bozman N, Gezici S, et al.
Association of TAP1 and TAP2 gene polymorphisms with hematological malignancies.
Asian Pac J Cancer Prev. 2013; 14(9):5213-7 [PubMed] Related Publications
Transporter associated with antigen presenting (TAP) 1 and TAP2 genes are localized in the major histocompatability complex (MHC) class II region and form a heterodimer playing a key role in endogenous pathways for antigen presentation. Defects of these genes have been reported to be common in different types of cancer. Polymorphisms identified in these loci have also been investigated and reported to be associated with several autoimmune disorders, viral infections and neoplasms. In the present study, for the first time, the allele and genotype frequencies of TAP1-333, TAP2-565, TAP2-651 and TAP2-665 were determined in patients with hematological malignancies (HM) using a PCR-RFLP method and compared with the frequencies in the control group. Our results suggested an association of TAP1-333 polymorphism with multiple myeloma-MM and TAP2- 565 polymorphism with chronic lymphoid leukemia-CLL. In addition, it could be concluded that the TAP2-665 GG genotype might be a risk factor for all types of hematological malignancies included in this study.

Ren Y, Zhang Y, Liu RZ, et al.
JAK1 truncating mutations in gynecologic cancer define new role of cancer-associated protein tyrosine kinase aberrations.
Sci Rep. 2013; 3:3042 [PubMed] Free Access to Full Article Related Publications
Cancer-associated protein tyrosine kinase (PTK) mutations usually are gain-of-function (GOF) mutations that drive tumor growth and metastasis. We have found 50 JAK1 truncating mutations in 36 of 635 gynecologic tumors in the Total Cancer Care® (TCC®) tumor bank. Among cancer cell lines containing JAK1 truncating mutations in the Cancer Cell Line Encyclopedia databank, 68% are gynecologic cancer cells. Within JAK1 the K142, P430, and K860 frame-shift mutations were identified as hot spot mutation sites. Sanger sequencing of cancer cell lines, primary tumors, and matched normal tissues confirmed the JAK1 mutations and showed that these mutations are somatic. JAK1 mediates interferon (IFN)-γ-regulated tumor immune surveillance. Functional assays show that JAK1 deficient cancer cells are defective in IFN-γ-induced LMP2 and TAP1 expression, loss of which inhibits presentation of tumor antigens. These findings identify recurrent JAK1 truncating mutations that could contribute to tumor immune evasion in gynecologic cancers, especially in endometrial cancer.

Leone P, Shin EC, Perosa F, et al.
MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells.
J Natl Cancer Inst. 2013; 105(16):1172-87 [PubMed] Related Publications
The surface presentation of peptides by major histocompatibility complex (MHC) class I molecules is critical to all CD8(+) T-cell adaptive immune responses, including those against tumors. The generation of peptides and their loading on MHC class I molecules is a multistep process involving multiple molecular species that constitute the so-called antigen processing and presenting machinery (APM). The majority of class I peptides begin as proteasome degradation products of cytosolic proteins. Once transported into the endoplasmic reticulum by TAP (transporter associated with antigen processing), peptides are not bound randomly by class I molecules but are chosen by length and sequence, with peptidases editing the raw peptide pool. Aberrations in APM genes and proteins have frequently been observed in human tumors and found to correlate with relevant clinical variables, including tumor grade, tumor stage, disease recurrence, and survival. These findings support the idea that APM defects are immune escape mechanisms that disrupt the tumor cells' ability to be recognized and killed by tumor antigen-specific cytotoxic CD8(+) T cells. Detailed knowledge of APM is crucial for the optimization of T cell-based immunotherapy protocols.

Hlaváč V, Brynychová V, Václavíková R, et al.
The expression profile of ATP-binding cassette transporter genes in breast carcinoma.
Pharmacogenomics. 2013; 14(5):515-29 [PubMed] Related Publications
AIM: ATP-binding cassette (ABC) transporters contribute to development of resistance to anticancer drugs via ATP-dependent drug efflux. A major goal of our study was to investigate associations between the expression of ABC transporters and outcome of breast carcinoma patients.
PATIENTS & METHODS: Transcript levels of all 49 human ABC transporters were determined in post-treatment tumor and non-neoplastic tissue samples from 68 breast carcinoma patients treated by neoadjuvant chemotherapy. Six ABC transporters were then evaluated in independent series of 100 pretreatment patients.
RESULTS: ABCA5/6/8/9/10, ABCB1/5/11, ABCC6/9, ABCD2/4, ABCG5 and ABCG8 were significantly downregulated and ABCA2/3/7/12, ABCB2/3/8/9/10, ABCC1/4/5/10/11/12, ABCD1/3, ABCE1, ABCF1/2/3 and ABCG1 were upregulated in post-treatment tumors compared with non-neoplastic tissues. Significant associations of intratumoral levels of ABCC1 and ABCC8 with grade and expression of hormonal receptors were found in both sets of patients. ABCA12, ABCA13 and ABCD2 levels were significantly associated with the response to neoadjuvant chemotherapy in post-treatment patients. Protein expression of ABCA12, ABCC8 and ABCD2 in tumor tissues of patients with breast carcinoma was observed by immunoblotting for the first time.
CONCLUSION: ABCA12, ABCA13, ABCC1, ABCC8 and ABCD2 present potential modifiers of progression and response to the chemotherapy of breast carcinoma.

Xu M, Li L, Liu Z, et al.
ABCB2 (TAP1) as the downstream target of SHH signaling enhances pancreatic ductal adenocarcinoma drug resistance.
Cancer Lett. 2013; 333(2):152-8 [PubMed] Related Publications
Hedgehog signaling plays critical roles in drug resistance of PDAC. We demonstrate that SHH is highly expressed in PDAC patients and cell lines. SHH signaling protects PDAC cells against gemcitabine induced apoptosis, because either over-expression or knockdown of SHH in PDAC cells affects the sensitivity to gemcitabine. Mechanistic studies show that ABCB2 serves as the downstream target of SHH signaling, leading to the drug resistance of PDAC cells. Combinational treatments with gemcitabine and cyclopamine yield synergistic antitumor effects in vitro and in vivo. Our study suggests that inhibiting SHH signaling or targeting ABCB2 gene improves the efficacy of chemotherapy in patients with PDAC.

El Hage F, Durgeau A, Mami-Chouaib F
TAP expression level in tumor cells defines the nature and processing of MHC class I peptides for recognition by tumor-specific cytotoxic T lymphocytes.
Ann N Y Acad Sci. 2013; 1283:75-80 [PubMed] Related Publications
We identified that the antigen preprocalcitonin (ppCT) is recognized on a human lung carcinoma by a cytotoxic T lymphocyte clone derived from autologous tumor-infiltrating lymphocytes. The antigenic peptide ppCT(16-25) is encoded by the gene calcitonin-related polypeptide alpha (CALCA), which codes for CT and is overexpressed in several lung carcinomas compared with normal tissues. The ppCT peptide is derived from the C-terminal region of the signal peptide and is processed independently of proteasomes and the transporter associated with antigen processing (TAP)1/TAP2 heterodimeric complexes. Instead, processing occurs within the endoplasmic reticulum by a novel mechanism involving signal pepsidase (SP) and signal peptide peptidase (SPP). Although lung cancer cells bearing the ppCT(16-25) epitope displayed low levels of TAP, restoration of TAP expression by interferon (IFN)-γ treatment or by TAP1/TAP2 gene transfer inhibited ppCT antigen presentation. Thus, the ppCT(16-25) human tumor epitope requires low TAP expression for efficient presentation. These results indicate that emerging SP-generated peptides represent alternative T cell targets that permit cytotoxic T lymphocytes to destroy TAP-impaired tumors, a process that helps to overcome tumor escape from CD8(+) T cell immunity. Additionally, our data suggest that ppCT is a promising candidate for cancer immunotherapy.

Sakulterdkiat T, Srisomsap C, Udomsangpetch R, et al.
Curcumin resistance induced by hypoxia in HepG2 cells is mediated by multidrug-resistance-associated proteins.
Anticancer Res. 2012; 32(12):5337-42 [PubMed] Related Publications
BACKGROUND: Tumor hypoxia, a common pathophysiological feature of solid tumors, contributes to drug resistance and treatment failure. Here, we demonstrate that hypoxia in HepG2 cells induces resistance towards cytotoxicity of curcumin, a promising anticancer agent.
MATERIALS AND METHODS: The number of surviving cells after exposure to chemotherapeutic drugs under normoxia (ambient O(2)) and hypoxia (1% O(2)) was determined by crystal violet staining. The expression levels of drug transporter genes were analyzed by quantitative real-time reverse transcription-polymerase chain reaction.
RESULTS: Increased resistance to curcumin, as well as to etoposide and doxorubicin, was observed in HepG2 cells under hypoxia. Gene expression analysis revealed that hypoxia increased the expression of ATP-binding cassette (ABC) drug transporter genes, sub-family C including ABCC1, ABCC2, and ABCC3, by more than two-fold. While expression of ABC drug transporter genes sub-family B member 1 and sub-family G member 2 (ABCB2/P-gp and ABCG2, respectively) did not change significantly. Both inhibitors of ABCC1/ABCC2 and depletion of intracellular glutathione levels were able to reverse hypoxia-induced curcumin resistance.
CONCLUSION: ABCC1 and ABCC2 play an important role in hypoxia-induced curcumin resistance in human hepatocellular carcinoma.

Williams BJ, Bhatia S, Adams LK, et al.
Dendritic cell based PSMA immunotherapy for prostate cancer using a CD40-targeted adenovirus vector.
PLoS One. 2012; 7(10):e46981 [PubMed] Free Access to Full Article Related Publications
Human prostate tumor vaccine and gene therapy trials using ex vivo methods to prime dendritic cells (DCs) with prostate specific membrane antigen (PSMA) have been somewhat successful, but to date the lengthy ex vivo manipulation of DCs has limited the widespread clinical utility of this approach. Our goal was to improve upon cancer vaccination with tumor antigens by delivering PSMA via a CD40-targeted adenovirus vector directly to DCs as an efficient means for activation and antigen presentation to T-cells. To test this approach, we developed a mouse model of prostate cancer by generating clonal derivatives of the mouse RM-1 prostate cancer cell line expressing human PSMA (RM-1-PSMA cells). To maximize antigen presentation in target cells, both MHC class I and TAP protein expression was induced in RM-1 cells by transduction with an Ad vector expressing interferon-gamma (Ad5-IFNγ). Administering DCs infected ex vivo with CD40-targeted Ad5-huPSMA, as well as direct intraperitoneal injection of the vector, resulted in high levels of tumor-specific CTL responses against RM-1-PSMA cells pretreated with Ad5-IFNγ as target cells. CD40 targeting significantly improved the therapeutic antitumor efficacy of Ad5-huPSMA encoding PSMA when combined with Ad5-IFNγ in the RM-1-PSMA model. These results suggest that a CD-targeted adenovirus delivering PSMA may be effective clinically for prostate cancer immunotherapy.

Hasim A, Abudula M, Aimiduo R, et al.
Post-transcriptional and epigenetic regulation of antigen processing machinery (APM) components and HLA-I in cervical cancers from Uighur women.
PLoS One. 2012; 7(9):e44952 [PubMed] Free Access to Full Article Related Publications
Normal function of human leukocyte antigen class I (HLA-I) and antigen processing machinery (APM) proteins is required for T cell-mediated anti-tumor or antiviral immunity, whereas the tumor survival indicates a failure of the host in immune surveillance associated with the dysfunction in antigen presentation, mainly due to the deregulation in HLA-I and APM expression or function. The posttranscriptional regulation of HLA-I and APM expression may associate with epigenetic modifications in cancer development which was not described so far. Here we showed that the development of cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma (CSCC) in Uighur women was accompanied with the partial or total loss of protein expression of HLA-I, ß2-m and APM components, including the transporter associated with antigen processing (TAP1/2), low molecular mass protein (LMP2, LMP7), endoplasmic reticulum aminopeptidase 1(ERAP1), chaperone molecules include calreticulin (CLR), calnexin (CNX) and ERp57, and this was proved again by analysis of transcription of the same genes in addition to three genes HLA-A, B and C coding for HLA-I. By bisulfite sequencing approach, we identified target CpG islands methylated at the gene promoter region of TAP1, TAP2, LMP7, tapasin and ERp57 in cervical carcinoma cells. Further analysis of CpG site specific methylation of these genes in cases of CSCC and CIN demonstrated an inverse correlation of altered CpG island methylation of TAP1, LMP7, and ERp57 with changes in protein expression. Moreover, promoter methylation of these genes was significantly higher in cases positive for human papillomavirus 16 (HPV 16) than negative ones. Our results suggested that epigenetic modifications are responsible for the aberrant expression of certain HLA-I and APM genes, and may help to understand unrevealed mechanisms of tumor escape from immune surveillance in cervical carcinogenesis.

Qiu B, Huang B, Wang X, et al.
Association of TAP1 and TAP2 polymorphisms with the outcome of persistent HBV infection in a northeast Han Chinese population.
Scand J Gastroenterol. 2012; 47(11):1368-74 [PubMed] Related Publications
OBJECTIVE: Transporter associated with antigen processing (TAP) plays a central role in a cellular immune response against HBV. Polymorphisms exist at the coding region of TAP and alter its structure and function. The aim of this study was to evaluate the potential relationship between polymorphisms of TAP and different outcomes of persistent HBV infection in a Han population in northeastern China.
MATERIAL AND METHODS: 189 HBV spontaneously recovered (SR) subjects, 571 HBV-infected patients including 180 chronic hepatitis B (CHB), 196 liver cirrhosis (LC) and 195 hepatocellular carcinoma (HCC) individuals were included in this study. TAP1-333 Ile/Val and -637 Asp/Gly, TAP2-651 Arg/Cys and -687 Stop/Gln were genotyped in all the samples by using a PCR-RFLP method.
RESULTS: The frequency of TAP1-637-Gly (allele G) was significantly higher in persistently HBV-infected individuals (CHB and LC) than that of SR subjects (OR = 1.58, 95% CI 1.12-2.45, p = 0.024; OR = 1.78, 95% CI 1.27-2.68, p = 0.002) by a logistic regression analysis. In addition, the statistically significant difference in the distribution of TAP2-651-Cys (allele T) was observed between HCC cases and SR controls (OR = 2.30, 95% CI 1.51-3.72, p < 0.001), and TAP2-687-Gln (allele C) in CHB patients was more common than that in SR subjects (OR = 1.41, 95% CI 1.13-1.97, p = 0.021). The data also revealed that haplotype 687 Gln-651 Cys-637 Gly-333 Ile was strongly associated with persistent HBV infection (CHB, LC and HCC) (p < 0.001, < 0.05 and < 0.001, respectively).
CONCLUSION: These results suggested that TAP variants were likely to play a substantial role in different outcomes of persistent HBV infection in the studied population.

Ma Z, Guo W, Niu HJ, et al.
Transcriptome network analysis reveals potential candidate genes for esophageal squamous cell carcinoma.
Asian Pac J Cancer Prev. 2012; 13(3):767-73 [PubMed] Related Publications
The esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with a poor prognosis. Understanding molecular changes in ESCC should improve identification of risk factors with different molecular subtypes and provide potential targets for early detection and therapy. Our study aimed to obtain a molecular signature of ESCC through the regulation network based on differentially expressed genes (DEGs). We used the GSE23400 series to identify potential genes related to ESCC. Based on bioinformatics we constructed a regulation network. From the results, we could establish that many transcription factors and pathways closely related with ESCC were linked by our method. STAT1 also arose as a hub node in our transcriptome network, along with some transcription factors like CCNB1, TAP1, RARG and IFITM1 proven to be related with ESCC by previous studies. In conclusion, our regulation network provided information on important genes which might be useful in investigating the complex interacting mechanisms underlying the disease.

Poage GM, Butler RA, Houseman EA, et al.
Identification of an epigenetic profile classifier that is associated with survival in head and neck cancer.
Cancer Res. 2012; 72(11):2728-37 [PubMed] Free Access to Full Article Related Publications
Panels of prognostic biomarkers selected using candidate approaches often do not validate in independent populations, so additional strategies are needed to identify reliable classifiers. In this study, we used an array-based approach to measure DNA methylation and applied a novel method for grouping CpG dinucleotides according to well-characterized genomic sequence features. A hypermethylation profile among 13 CpG loci, characterized by polycomb group target genes, mammalian interspersed repeats, and transcription factor-binding sites (PcG/MIR/TFBS), was associated with reduced survival (HR, 3.98; P = 0.001) in patients with head and neck squamous cell carcinoma. This association was driven by CpGs associated with the TAP1 and ALDH3A1 genes, findings that were validated in an independent patient group (HR, 2.86; P = 0.04). Together, the data not only elucidate new potential targets for therapeutic intervention in head and neck cancer but also may aid in the identification of poor prognosis patients who may require more aggressive treatment regimens.

Lu F, Tsai K, Chen HS, et al.
Identification of host-chromosome binding sites and candidate gene targets for Kaposi's sarcoma-associated herpesvirus LANA.
J Virol. 2012; 86(10):5752-62 [PubMed] Free Access to Full Article Related Publications
LANA is essential for tethering the Kaposi's sarcoma-associated herpesvirus (KSHV) genome to metaphase chromosomes and for modulating host-cell gene expression, but the binding sites in the host-chromosome remain unknown. Here, we use LANA-specific chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-Seq) to identify LANA binding sites in the viral and host-cell genomes of a latently infected pleural effusion lymphoma cell line BCBL1. LANA bound with high occupancy to the KSHV genome terminal repeats (TR) and to a few minor binding sites in the KSHV genome, including the LANA promoter region. We identified 256 putative LANA binding site peaks with P < 0.01 and overlap in two independent ChIP-Seq experiments. We validated several of the high-occupancy binding sites by conventional ChIP assays and quantitative PCR. Candidate cellular LANA binding motifs were identified and assayed for binding to purified recombinant LANA protein in vitro but bound with low affinity compared to the viral TR binding site. More than half of the LANA binding sites (170/256) could be mapped to within 2.5 kb of a cellular gene transcript. Pathways and Gene Ontogeny (GO) analysis revealed that LANA binds to genes within the p53 and tumor necrosis factor (TNF) regulatory network. Further analysis revealed partial overlap of LANA and STAT1 binding sites in several gamma interferon (IFN-γ)-regulated genes. We show that ectopic expression of LANA can downmodulate IFN-γ-mediated activation of a subset of genes, including the TAP1 peptide transporter and proteasome subunit beta type 9 (PSMB9), both of which are required for class I antigen presentation. Our data provide a potential mechanism through which LANA may regulate several host cell pathways by direct binding to gene regulatory elements.

Zhao X, Sun Q, Tian H, et al.
Loss of heterozygosity at 6p21 and HLA class I expression in esophageal squamous cell carcinomas in China.
Asian Pac J Cancer Prev. 2011; 12(10):2741-5 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: The loss or downregulation of human leukocyte antigen ( HLA-I) has been proposed to contribute to immune evasion by cancer cells. Since the human leukocyte antigen (HLA-I) complex is located at 6p21.3, loss of heterozygosity of this region may alter HLA class I tumor phenotypes. The aim of this study was to analysis loss of heterozygosity (LOH) of chromosome 6p in ESCC samples and correlate this with HLA class I expression.
MATERIALS AND METHODS: A total of 87 formalin-fixed, paraffin-embeded and frozen-fresh of ECSS lesions were collected. HLA-Iand antigen-processing machinery component expression was investigated by immunohistochemistry with anti-HLA class I monoclonal antibody and a panel of 49 ESCCs with downregulated HLA class I expression were selected for LOH studies using 3 microsatellite markers located at 6p21.3 (D6S105,D6S265,D6S273).
RESULTS: HLA-Iantigen,TAP1 and LMP were lost or down-regulated in 57.5, 29.8 and 47.0% of the ESCC lesions, respectively. In 23/49(46.9%) of the ESCCs, allelic loss for at least one locus at 6p21.3 was found.
CONCLUSIONS: Our data show that downregulation of HLA class I expression is correlated with loss of heterozygosity regions at 6p21.3 in ESCC.

Raafat N, Sadowski-Cron C, Mengus C, et al.
Preventing vaccinia virus class-I epitopes presentation by HSV-ICP47 enhances the immunogenicity of a TAP-independent cancer vaccine epitope.
Int J Cancer. 2012; 131(5):E659-69 [PubMed] Related Publications
Herpes simplex virus protein ICP47, encoded by US12 gene, strongly downregulates major histocompatibility complex (MHC) class-I antigen restricted presentation by blocking transporter associated with antigen processing (TAP) protein. To decrease viral vector antigenic immunodominance and MHC class-I driven clearance, we engineered recombinant vaccinia viruses (rVV) expressing ICP47 alone (rVV-US12) or together with endoplasmic reticulum (ER)-targeted Melan-A/MART-1(27-35) model tumor epitope (rVV-MUS12). In this study, we show that antigen presenting cells (APC), infected with rVV-US12, display a decreased ability to present TAP dependent MHC class-I restricted viral antigens to CD8+ T-cells. While HLA class-I cell surface expression is strongly downregulated, other important immune related molecules such as CD80, CD44 and, most importantly, MHC class-II are unaffected. Characterization of rVV-MUS12 infected cells demonstrates that over-expression of a TAP-independent peptide, partially compensates for ICP47 induced surface MHC class-I downregulation (30% vs. 70% respectively). Most importantly, in conditions where clearance of infected APC by virus-specific CTL represents a limiting factor, a significant enhancement of CTL responses to the tumor epitope can be detected in cultures stimulated with rVV-MUS12, as compared to those stimulated by rVV-MART alone. Such reagents could become of high relevance in multiple boost protocols required for cancer immunotherapy, to limit vector-specific responsiveness.

Fellerhoff B, Gu S, Laumbacher B, et al.
The LMP7-K allele of the immunoproteasome exhibits reduced transcript stability and predicts high risk of colon cancer.
Cancer Res. 2011; 71(23):7145-54 [PubMed] Related Publications
Destruction of cancer cells by cytotoxic T lymphocytes depends on immunogenic tumor peptides generated by proteasomes and presented by human leukocyte antigen (HLA) molecules. Functional differences arising from alleles of immunoproteasome subunits have not been recognized so far. We analyzed the genetic polymorphism of the immunoproteasome subunits LMP2 and LMP7 and of the transporters associated with antigen processing (TAP1 and TAP2) in two independently collected panels of colorectal carcinoma patients (N(1) = 112, N(2) = 62; controls, N = 165). High risk of colon cancer was associated with the LMP7-K/Q genotype (OR = 8.10, P = 1.10 × 10(-11)) and low risk with the LMP7-Q/Q genotype (OR = 0.10, P = 5.97 × 10(-13)). The basis for these distinct associations of LMP7 genotypes was functionally assessed by IFN-γ stimulation of colon carcinoma cell lines (N = 10), followed by analyses of mRNA expression of HLA class I, TAP1, TAP2, and LMP7, with real-time PCR. Whereas induction of HLA-B, TAP1, and TAP2 was comparable in all cell lines, transcript amounts of LMP7-Q increased 10-fold, but of LMP7-K only 3.8-fold. This correlated with a reduced transcript stability of LMP7-K (t(1/2) ≈ 7 minutes) compared with LMP7-Q (t(1/2) ≈ 33 minutes). In addition, LMP7-Q/Q colon carcinoma cells increased (the peptide based) HLA class I surface expression significantly after IFN-γ stimulation, whereas LMP7-Q/K and LMP7-K/K carcinoma cells showed minimal (<20%) changes. These results suggest that the presence of LMP7-K can reduce the formation of immunoproteasomes and thus peptide processing, followed by reduced peptide-HLA presentation, a crucial factor in the immune response against cancer.

Durgeau A, El Hage F, Vergnon I, et al.
Different expression levels of the TAP peptide transporter lead to recognition of different antigenic peptides by tumor-specific CTL.
J Immunol. 2011; 187(11):5532-9 [PubMed] Related Publications
Decreased antigenicity of cancer cells is a major problem in tumor immunology. This is often acquired by an expression defect in the TAP. However, it has been reported that certain murine Ags appear on the target cell surface upon impairment of TAP expression. In this study, we identified a human CTL epitope belonging to this Ag category. This epitope is derived from preprocalcitonin (ppCT) signal peptide and is generated within the endoplasmic reticulum by signal peptidase and signal peptide peptidase. Lung cancer cells bearing this antigenic peptide displayed low levels of TAP, but restoration of their expression by IFN-γ treatment or TAP1 and TAP2 gene transfer abrogated ppCT Ag presentation. In contrast, TAP upregulation in the same tumor cells increased their recognition by proteasome/TAP-dependent peptide-specific CTLs. Thus, to our knowledge, ppCT(16-25) is the first human tumor epitope whose surface expression requires loss or downregulation of TAP. Lung tumors frequently display low levels of TAP molecules and might thus be ignored by the immune system. Our results suggest that emerging signal peptidase-generated peptides represent alternative T cell targets, which permit CTLs to destroy TAP-impaired tumors and thus overcome tumor escape from CD8(+) T cell immunity.

Garcia-Donas J, Esteban E, Leandro-García LJ, et al.
Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study.
Lancet Oncol. 2011; 12(12):1143-50 [PubMed] Related Publications
BACKGROUND: Sunitinib is a tyrosine kinase inhibitor with proven efficacy in renal-cell carcinoma, but some patients do not respond or need dose reductions due to toxicity. Because there are no validated molecular predictors of response or toxicity to sunitinib, we aimed to identify genetic markers predictive of outcome and toxic effects.
METHODS: In our observational, prospective study we enrolled previously untreated adults (≥ 18 years) with clear-cell renal-cell carcinoma at 15 institutions in the Spanish Oncology Genitourinary Group in Spain. Patients received sunitinib according to local practice guidelines. We assessed RECIST response, progression-free survival (PFS), overall survival, and toxicity of sunitinib with 16 key polymorphisms in nine genes: VEGFR2 (rs2305948 and rs1870377), VEGFR3 (rs307826, rs448012, and rs307821), PDGFR-α (rs35597368), VEGF-A (rs2010963, rs699947, and rs1570360), IL8 (rs1126647), CYP3A4 (rs2740574), CYP3A5 (rs776746), ABCB1 (rs1045642, rs1128503, and rs2032582), and ABCB2 (rs2231142). We assessed associations with efficacy and toxicity by use of univariable and multivariable analyses (with clinical factors associated with outcomes as covariates). We adjusted for multiplicity using the Bonferroni method; p values of less than 0·0031 before adjustment were deemed to still be significant after adjustment.
FINDINGS: We enrolled 101 patients between Oct 10, 2007, and Dec 13, 2010. 95 of these patients were included in toxicity analyses and 89 in the efficacy analyses. Two VEGFR3 missense polymorphisms were associated with reduced PFS with sunitinib on multivariable analysis: rs307826 (hazard ratio [HR] per allele 3·57, 1·75-7·30; p(unadjusted)=0·00049, p(adjusted)=0·0079) and rs307821 (3·31, 1·64-6·68; p(unadjusted)=0·00085, p(adjusted)=0·014). The CYP3A5*1 (rs776746) high metabolising allele was associated in a multivariable analysis with an increased risk of dose reductions due to toxicity (HR per allele 3·75, 1·67-8·41; p(unadjusted)=0·0014, p(adjusted)=0·022). No other SNPs were associated with sunitinib response or toxicity.
INTERPRETATION: Polymorphisms in VEGFR3 and CYP3A5*1 might be able to define a subset of patients with renal-cell carcinoma with decreased sunitinib response and tolerability. If confirmed, these results should promote interventional studies testing alternative therapeutic approaches for patients with such variants.
FUNDING: Pfizer.

Bormann F, Sers C, Seliger B, et al.
Methylation-specific ligation detection reaction (msLDR): a new approach for multiplex evaluation of methylation patterns.
Mol Genet Genomics. 2011; 286(3-4):279-91 [PubMed] Related Publications
A new sensitive method for multiplex gene-specific methylation analysis was developed using a ligation-based approach combined with a TaqMan-based detection and readout employing universal reporter probes. The approach, termed methylation-specific Ligation Detection Reaction (msLDR), was applied to test 16 loci in 8 different colorectal cancer cells in parallel. These loci encode immune regulatory genes involved in T-cell and natural killer cell activation, whose silencing is associated with the development or progression of colorectal cancer. Parallel analysis of HLA-A, HLA-B, STAT1, B2M, LMP2, LMP7, PA28α, TAP1, TAP2, TAPBP, ULBP2 and ULBP3 by msLDR in eight colorectal cancer cell lines showed preferential methylation at the HLA-B, ULBP2 and ULBB3 loci, but not at the other loci. MsLDR was found to represent a suitable and sensitive method for the detection of distinct methylation patterns as validated by conventional bisulphite Sanger sequencing and COBRA analysis. Since gene silencing by epigenetic mechanisms plays a central role during transformation of a normal differentiated somatic cell into a cancer cell, characterization of the gene methylation status in tumours is a major topic not only in basic research, but also in clinical diagnostics. Due to a very simple workflow, msLDR is likely to be applicable to clinical samples and thus comprises a potential diagnostic tool for clinical purposes.

Wu TH, Schreiber K, Arina A, et al.
Progression of cancer from indolent to aggressive despite antigen retention and increased expression of interferon-gamma inducible genes.
Cancer Immun. 2011; 11:2 [PubMed] Free Access to Full Article Related Publications
Many cancers escape host immunity without losing tumor-specific rejection antigens or MHC class I expression. This study tracks the evolution of one such cancer that developed in a mouse following exposure to ultraviolet light. The primary autochthonous tumor was not highly malignant and was rejected when transplanted into naïve immunocompetent mice. Neoplastic cells isolated from the primary tumor were susceptible to the growth-inhibitory effects of IFNγ in vitro, but expressed very low levels of MHC I antigen and were resistant to tumor-specific T cells unless they were first exposed to IFNγ. Serial passage of the primary tumor cells in vivo led to a highly aggressive variant that caused fast-growing tumors in normal mice. In vitro, the variant tumor cells showed increased resistance to the growth-inhibitory effects of IFNγ but expressed high levels of immunoproteasomes and MHC I molecules and were susceptible to tumor-specific T cells even without prior exposure to IFNγ.

Wei H, Hongya P, Linlin J, et al.
IFN-γ enhances the anti-tumour immune response of dendritic cells against oral squamous cell carcinoma.
Arch Oral Biol. 2011; 56(9):891-8 [PubMed] Related Publications
OBJECTIVE: To investigate the expression of antigen processing-1 (Tap-1) and Tapasin in oral squamous cell carcinoma (OSCC), and observe the immune response against OSCC by use of IFN-γ-antigen induced dendritic cells (DCs) in vitro and in vivo.
DESIGN: Expression of Tap-1 and Tapasin in different cell lines was analysed. CAL27 cells were treated with IFN-γ. Antigen from the treated cells was presented by DCs. Pulsed DC was then co-cultivated with CD8+ T lymphocyte to induce antigen specific cytotoxic lymphocytes (CTLs). The immune response elicited by CTLs against OSCC was observed.
RESULTS: A significant lower expression of Tap-1 and Tapasin was observed in OSCC cell lines. IFN-γ exerted time-dependent effect for increasing the expression of these genes. Antigen from the treated CAL27 cells was presented by DCs. CTLs were induced and generated a strong immune response in vitro and in vivo.
CONCLUSIONS: Tap-1 and Tapasin were downregulated in OSCC. IFN-γ increased the expression of these genes. Use of IFN-γ-antigen induced DCs could induce stronger immune response in vitro and in vivo.

Qifeng S, Bo C, Xingtao J, et al.
Methylation of the promoter of human leukocyte antigen class I in human esophageal squamous cell carcinoma and its histopathological characteristics.
J Thorac Cardiovasc Surg. 2011; 141(3):808-14 [PubMed] Related Publications
OBJECTIVE: The downregulation of human leukocyte antigen class I (HLA-I) has been proposed to contribute to the immune evasion of cancer cells in some cancers. Meanwhile, transcriptional silencing by means of promoter methylation is now believed to be an important mechanism of carcinogenesis. The aim of this study was (1) to examine the expression of HLA-I antigen and the antigen-processing machinery components in patients with esophageal squamous cell carcinoma lesions and (2) to detect the methylation pattern of the HLA-I gene in patients with esophageal squamous cell carcinoma and assess its association with histopathological characteristics.
METHODS: A total of 87 formalin-fixed and paraffin-embedded esophageal squamous cell carcinoma lesions were collected. HLA-I and antigen-processing machinery component expression was investigated by means of immunohistochemistry with anti-HLA-I monoclonal antibody, and methylation changes in the promoter region of HLA-1 genes were determined by using methylation-specific polymerase chain reaction.
RESULTS: HLA-I, transporter associated with antigen processing 1, and low molecular weight protein were lost or downregulated in 67%, 29.8%, and 47.0% of the esophageal squamous cell carcinoma lesions, respectively. The positive rates of gene promoter hypermethylation of HLA-I was 70.1% (61/87) in tumor tissues compared with 3.6% in normal tissue (P < .01). Also, the higher methylation rates and the HLA-I expression were significantly associated with tumor grade, including lymph node metastasis (P < .05).
CONCLUSIONS: HLA-I promoter hypermethylation was associated with loss of HLA-I antigen, which frequently occurred in primary tumors, especially in metastatic lymph node lesions, and was associated with patients' prognoses.

Yamakawa Y, Hamada A, Nakashima R, et al.
Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia.
Ther Drug Monit. 2011; 33(2):244-50 [PubMed] Related Publications
This study explored the association of 14 single nucleotide polymorphisms in three genes coding for influx transporters (SLC22A1, SLCO1B1, and SLCO1B3), two genes coding for efflux transporters (ABCB1 and ABCG2), and four genes coding for enzymes (CYP2C9, CYP2C19, CYP2D6, and CYP3A5) with the pharmacokinetics of imatinib in Japanese patients with chronic myeloid leukemia. Pharmacokinetic parameters were estimated by a population pharmacokinetic analysis based on 622 plasma samples from 34 patients at steady state. Approximately 4.6-fold variability in individual clearance was observed (range, 3.4-15.5 L/hr). The individual estimated clearance was significantly increased in patients with the SLCO1B3 334GG genotype (median value ± standard deviation, 9.5 ± 3.1 L/hr; n = 19) compared with SLCO1B3 334TT and TG genotypes (7.0 ± 3.1 L/hr; n = 15) (P = 0.019). Patients with the ABCB1 3435CC genotype had significantly higher imatinib clearance (12.7 ± 3.0 L/hr; n = 7) compared with patients with ABCB1 3435CT and TT genotypes (7.9 ± 2.7 L/hr; n = 27) (P = 0.035). In conclusion, the present study suggests that single nucleotide polymorphisms of the influx transporter SLCO1B3 and the efflux transporter ABCB1 were functionally associated with individual variability of imatinib pharmacokinetics in Japanese patients with chronic myeloid leukemia.

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