The LMP7-K allele of the immunoproteasome exhibits reduced transcript stability and predicts high risk of colon cancer.
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.
Institute for Immunology, University of Munich, Germany. barbara.fellerhoff@med.uni-muenchen.de
Barbara
B
Fellerhoff
Songhai
S
Gu
Barbara
B
Laumbacher
Andreas G
AG
Nerlich
Elisabeth H
EH
Weiss
Jürgen
J
Glas
Reinhard
R
Kopp
Judith P
JP
Johnson
Rudolf
R
Wank
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology; D000328:Adult; D000368:Aged; D000483:Alleles; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D005787:Gene Frequency / Q000276:immunology; D005805:Genes, MHC Class I / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007125:Immunogenetics / Q000379:methods; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D011110:Polymorphism, Genetic; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D015235:HLA-B Antigens; D012333:RNA, Messenger; C073119:TAP1 protein, human; C071313:LMP-2 protein; C071692:TAP2 protein, human; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex