The LMP7-K Allele of the Immunoproteasome Exhibits Reduced Transcript Stability and Predicts High Risk of Colon Cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-12, Vol.71 (23), p.7145-7154
• Main Authors: FELLERHOFF, Barbara, SONGHAI GU, LAUMBACHER, Barbara, NERLICH, Andreas G, WEISS, Elisabeth H, GLAS, Jürgen, KOPP, Reinhard, JOHNSON, Judith P, WANK, Rudolf
• Format: Article
• Language: English
• Subjects: Adult; Aged; Alleles; Antineoplastic agents; ATP-Binding Cassette Sub-Family B Member 2; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - immunology; ATP-Binding Cassette, Sub-Family B, Member 3; Biological and medical sciences; Caco-2 Cells; Cell Line, Tumor; Colonic Neoplasms - genetics; Colonic Neoplasms - immunology; Colonic Neoplasms - pathology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - metabolism; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - immunology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic - immunology; Gene Frequency - immunology; Genes, MHC Class I - genetics; Genes, MHC Class I - immunology; Genetic Predisposition to Disease; Genotype; HeLa Cells; HLA-B Antigens - genetics; HLA-B Antigens - immunology; HT29 Cells; Humans; Immunogenetics - methods; Interferon-gamma - genetics; Interferon-gamma - immunology; Interferon-gamma - metabolism; Male; Medical sciences; Pharmacology. Drug treatments; Polymorphism, Genetic; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - immunology; RNA, Messenger - genetics; RNA, Messenger - immunology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-10-1883

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 (