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

Abstract

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 ¼ 112, N 2 ¼ 62; controls, N ¼ 165). High risk of colon cancer was associated with the LMP7-K/Q genotype (OR ¼ 8.10, P ¼ 1.10 Â 10 À11) and low risk with the LMP7-Q/Q genotype (OR ¼ 0.10, P ¼ 5.97 Â 10 -13 ). The basis for these distinct associations of LMP7 genotypes was functionally assessed by IFN-g stimulation of colon carcinoma cell lines (N ¼ 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 (t1 2 % 7 minutes) compared with LMP7-Q (t1 2 % 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 (<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. Cancer Res; 71(23); 7145-54. Ó2011 AACR.

Low Molecular Mass Polypeptide and Transporter Antigen Peptide Genes Polymorphism as the Risk Factors of Cervical Cancer Which Caused by Human Papillomavirus Type-16 Infection in Bali

“…Our study result was similar with the study of esophageal cancer and colon cancer, where they also did not find any correlation between TAP-1 and LMP-2 genes polymorphism with cancer incidence. 7,10 A study in Netherlands that was similar with our study showed that the decreasing expression of TAP-1 did not having correlation with the survival rate cervical cancer patients. 11 In the study that was conducted to know the expression of TAP-1 and LMP-2 upon mice, found that the tumor incidence was not different from the control group.…”

“…They also did not obtain LMP-2, TAP-1 and TAP-2 genes polymorphism in colon cancer. 10 There was a similar study with our study that was conducted in Netherlands and also investigating about cervical cancer specifically. They found that LMP-7 and TAP-2 genes polymorphism was correlated significantly with cervical cancer incidence in Dutch women.…”

Association between LMP2 and LMP7 gene polymorphisms and the risk of gastric cancer: A case-control study

“…The efficient expression of peptide-HLA complexes at the cell surface depends on the type and quantity of the peptides that are produced and processed (14). Overexpression of the LMP2 and LMP7 gene may lead to the production of an insufficient peptide level, which may allow cancer cells to escape immune processing, leading to GC development.…”

“…Several studies have reported an association between the genetic variants of Arg to His substitution at codon 60 of Association between LMP2 and LMP7 gene polymorphisms and the risk of gastric cancer: A case-control study LMP2 (LMP2-60) and Gln to Lys substitution at codon 145 of LMP7 (LMP7-145) and the risk of numerous malignant diseases, including ovarian cancer, colon cancer and esophageal carcinoma (13)(14)(15). However, the association between LMP2 and LMP7 polymorphisms and the risk of GC has not been investigated to date.…”

Proteasome expression and activity in cancer and cancer stem cells

“…Indeed, agreeing with this hypothesis, a polymorphism substituting glutamine for lysine in position 49 of the pro-sequence of PSMB8 (LMP7) unit, which leads to failure of the protein to be induced by interferon-γ (IFN-γ), was more prevalent in colon cancer patients than in healthy controls, suggesting that the failure of induction affects the ability of the immune system to mount an anticancer response. 36 Overall, these investigations associate low proteasome activity with populations of CSCs and with the ability to propagate tumors in vivo and resist treatment. The downregulation of proteasome activity may be a result of the low metabolic activity of stem cells that is associated with low cell cycling.…”