The LMP7-K Allele of the Immunoproteasome Exhibits Reduced Transcript Stability and Predicts High Risk of Colon Cancer
The LMP7-K Allele of the Immunoproteasome Exhibits Reduced Transcript Stability and Predicts High Risk of Colon Cancer
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DOI：
10.1158/0008-5472.can-10-1883
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发表时间：
2011-12-01
期刊：
影响因子：
11.2
通讯作者：
Wank, Rudolf
中科院分区：
文献类型：
--
作者：
Fellerhoff, Barbara;Gu, Songhai;Wank, Rudolf
细胞毒性T淋巴细胞对癌细胞的破坏依赖于由蛋白酶体产生并由人白细胞抗原（HLA）分子呈递的免疫原性肿瘤肽。免疫蛋白酶体亚基的等位基因引起的功能差异迄今尚未得到承认。我们分析了两组独立收集的结直肠癌患者（N（1）= 112，N（2）= 62;对照组，N = 165）中免疫蛋白酶体亚基LMP 2和LMP 7以及与抗原加工相关的转运蛋白（TAP 1和TAP 2）的遗传多态性。结肠癌的高风险与LMP 7-K/Q基因型相关（OR = 8.10，P = 1.10 × 10（-11）），而低风险与LMP 7-Q/Q基因型相关（OR = 0.10，P = 5.97 × 10（-13））。通过IFN-γ刺激结肠癌细胞系（N10），然后用实时PCR分析HLA I类、TAP 1、TAP 2和LMP 7的mRNA表达，在功能上评估LMP 7基因型的这些不同关联的基础。尽管HLA-B、TAP 1和TAP 2的诱导在所有细胞系中相当，但LMP 7-Q的转录量增加了10倍，但LMP 7-K仅增加了3.8倍。这与LMP 7-K（t（1/2）约为7分钟）与LMP 7-Q（t（1/2）约为33分钟）相比降低的转录物稳定性相关。此外，LMP 7-Q/Q结肠癌细胞在IFN-γ刺激后显著增加了（基于肽的）HLA I类表面表达，而LMP 7-Q/K和LMP 7-K/K癌细胞在IFN-γ刺激后显示出最小的（
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 x 10(-11)) and low risk with the LMP7-Q/Q genotype (OR = 0.10, P = 5.97 x 10(-13)). The basis for these distinct associations of LMP7 genotypes was functionally assessed by IFN-gamma 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) approximate to 7 minutes) compared with LMP7-Q (t(1/2) approximate to 33 minutes). In addition, LMP7-Q/Q colon carcinoma cells increased (the peptide based) HLA class I surface expression significantly after IFN-g stimulation, whereas LMP7-Q/K and LMP7-K/K carcinoma cells showed minimal (