1. ¹First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
2. ²Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Sapporo 060-8543, Japan
3. ³PRESTO JST, Kawaguchi 332-0012, Japan
4. ⁴Department of Pathology, Sapporo Medical University, Sapporo 060-8556, Japan
5. ⁵Division of Molecular Biology and Genetics, Saga Medical School, Saga 849-8501, Japan
6. ⁶Department of Biochemistry II, Nagoya University School of Medicine, Nagoya 466-0065, Japan
7. ⁷Central Animal Laboratory, National Cancer Center Research Institute, Tokyo 104-0045, Japan
8. ⁸Department of Clinical Laboratory Science, Yamaguchi University School of Medicine, Yamaguchi 755-8505, Japan
9. ⁹Keiyukai Sapporo Hospital, Sapporo 003-0027, Japan

Correspondence: M Toyota, First Department of Internal Medicine, Sapporo Medical University, South 1, West 16, Chuo-ku, Sapporo 060-8543, Japan. E-mail: mtoyota@sapmed.ac.jp

Received 16 December 2003; Revised 22 July 2004; Accepted 13 August 2004; Published online 4 October 2004.

Abstract

Tightly regulated at the level of transcription, expression of MHC class II molecules varies significantly among gastrointestinal cancers. High levels of MHC class II expression are often associated with a better prognosis, which is indicative of the involvement of CD4⁺ lymphocytes in tumor suppression, but the molecular mechanism by which MHC class II expression is regulated remains unclear. In the present study, we investigated the expression of one inducible MHC class II molecule, HLA-DR, and its coactivators in a panel of colorectal and gastric cancer cell lines. Interferon- induced expression of HLA-DR in 14 of 20 cell lines tested; the remaining six cell lines did not express HLA-DR. Analysis of the expression of transcription factors and coactivators associated with HLA-DR revealed that the loss of CIITA expression was closely associated with the absence of HLA-DR induction. Moreover, DNA methylation of the 5' CpG island of CIITA-PIV was detected in all cancer cells that lacked CIITA. The methylation and resultant silencing of CIITA-PIV depended on the activities of two DNA methyltransferases, DNMT1 and DNMT3B, and their genetic inactivation restored CIITA-PIV expression. It thus appears that CIITA methylation is a key mechanism that enables some gastrointestinal cancer cells to escape immune surveillance.