Colorectal tumorigenesis has been associated with the progressive acquisition of a variety of genetic alterations. These include mutations of the Ki-ras proto-oncogene in codons 12 and 13, which account for 85% of genetic changes in colorectal cancer. In murine in vitro models of oncogenic transformation, an association between ras-mediated transformation and downregulation of different components of the MHC class I antigen processing machinery (APM) has been described. In order to investigate whether this association also exists in human tumors, 10 cases of high-grade intraepithelial neoplasia (HIN), as well as primary tumors and autologous lymph node metastases from 42 patients with colorectal carcinoma, were monitored by allele-specific restriction analysis for Ki-ras mutations. In parallel, APM component expression and tumor cell proliferation were analyzed by immunohistochemistry. In comparison to autologous colorectal mucosa, TAP1, LMP2 and tapasin loss was found in 68%, 67% and 80% of HIN, respectively. In contrast, impaired TAP1, LMP2 and tapasin expression was found in 42%, 42% and 63% of primary adenocarcinomas of stage III disease and in 63%, 47% and 79% of the matched lymph node metastases, respectively. More than 60% of colorectal tumor lesions with TAP1, LMP2 and/or tapasin defects displayed Ki-ras mutations. The frequency of TAP1, LMP2 and tapasin loss varied between 33% of primary adenocarcinomas, 40% of HIN to approximately 67% of metastases. These data suggest that i) APM component deficiencies occur more frequently in Ki-ras-mutated colorectal carcinoma lesions and ii) APM abnormalities in conjunction with Ki-ras mutations appear to be associated with disease stage. These findings support the hypothesis that Ki-ras mutations may contribute to immune escape mechanisms of tumors by downregulating the MHC class I APM component expression. © 2003 Wiley-Liss, Inc. Key words: ras; MHC; colorectal cancer; antigen processingImmune responses against tumors are mainly based on the activation of cytotoxic CD8 ϩ T lymphocytes (CTL), which recognize endogenously generated and processed antigenic peptides in the context of MHC class I molecules. The classical MHC class I antigen processing and presentation pathway involves protein degradation mediated by the multimeric proteasome complex, particularly the interferon (IFN)-␥ inducible subunits LMP2, LMP7 and LMP10. 1,2 The yielded peptides are then translocated across the endoplasmic reticulum (ER) membrane via the ATPdependent heterodimeric transporters associated with antigen processing subunits TAP1 and TAP2. [3][4][5] In the ER, the assembly of newly synthesized MHC class I heavy chain (HC) molecules with  2 -microglobulin ( 2 -m) and peptide is assisted by transient interactions with a number of ER-resident chaperones. These include calnexin, calreticulin, protein disulfide isomerase, the thioloxidoreductase ER60 and tapasin. 6 During peptide loading, a multimeric TAP complex is formed that consists of both TAP subunits, the MHC class I antigens, calr...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.