Strong HLA-DR Antigen Expression on Cancer Cells Relates to Better Prognosis of Colorectal Cancer Patients: Possible Involvement of C-myc Suppression by Interferon-gamma in Situ

Overview

Journal Cancer Sci

Specialty Oncology

Date 2005 Dec 22

PMID 16367922

Citations 35

Authors

Kazuyuki Matsushita

Toshinao Takenouchi

Hideaki Shimada

Takeshi Tomonaga

Hideki Hayashi

Ayumi Shioya

Aki Komatsu

Hisahiro Matsubara

Takenori Ochiai

Affiliations

Soon will be listed here.

Abstract

Strong HLA-DR antigen expression on cancer cells relates to better prognosis of colorectal cancer patients, although the precise mechanism is controversial. From an immunological point of view, HLA-DR antigen, induced by interferon (IFN)-gamma, is required for tumor-associated antigen recognition by CD4(+) T cells. For instance, as reported previously, the expression of HLA-DR antigen in normal colorectal epithelium immediately adjacent to cancer coincided significantly with the existence of IFN-gamma mRNA in the tissue. From another aspect, IFN-gamma has been revealed to suppress c-myc expression in vivo through a stat1-dependent mechanism, which is important for cell growth, cell cycle and chromosome instability. In the present study, strong HLA-DR-positive expression on cancer cells was significantly related to better prognosis for colorectal cancer patients. High IFN-gamma mRNA expression in situ indicated significantly less activation of c-myc mRNA expression. Further, HLA-DR antigen expression in cancer cells, as well as Dukes stages, was an independent factor for better long-term survival by multivariate analysis. Taken together, IFN-gamma, which induces HLA-DR antigens on the cell surface, also suppresses c-myc expression in situ, and is a possible non-immunological mechanism involved in the better long-term survival of colorectal cancer patients.

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References

Ramana C, Grammatikakis N, Chernov M, Nguyen H, Goh K, Williams B . Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways. EMBO J. 2000; 19(2):263-72. PMC: 305560. DOI: 10.1093/emboj/19.2.263. View

Andersen S, Rognum T, Lund E, Meling G, Hauge S . Strong HLA-DR expression in large bowel carcinomas is associated with good prognosis. Br J Cancer. 1993; 68(1):80-5. PMC: 1968312. DOI: 10.1038/bjc.1993.290. View

Carlberg A, Moberg K, Hall D . Tumor necrosis factor and gamma-interferon repress transcription from the c-myc P2 promoter by reducing E2F binding activity. Int J Oncol. 1999; 15(1):121-6. DOI: 10.3892/ijo.15.1.121. View

Pelengaris S, Khan M, Evan G . Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell. 2002; 109(3):321-34. DOI: 10.1016/s0092-8674(02)00738-9. View

Diederichsen A, Hjelmborg J, Christensen P, Zeuthen J, Fenger C . Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells. Cancer Immunol Immunother. 2003; 52(7):423-8. PMC: 11032970. DOI: 10.1007/s00262-003-0388-5. View

Secombe J, Pierce S, Eisenman R . Myc: a weapon of mass destruction. Cell. 2004; 117(2):153-6. DOI: 10.1016/s0092-8674(04)00336-8. View

Shachaf C, Kopelman A, Arvanitis C, Karlsson A, Beer S, Mandl S . MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature. 2004; 431(7012):1112-7. DOI: 10.1038/nature03043. View

Nagy B, Lundan T, Larramendy M, Aalto Y, Zhu Y, Niini T . Abnormal expression of apoptosis-related genes in haematological malignancies: overexpression of MYC is poor prognostic sign in mantle cell lymphoma. Br J Haematol. 2003; 120(3):434-41. DOI: 10.1046/j.1365-2141.2003.04121.x. View

Ishii N, Chiba M, Iizuka M, Horie Y, Masamune O . Induction of HLA-DR antigen expression on human colonic epithelium by tumor necrosis factor-alpha and interferon-gamma. Scand J Gastroenterol. 1994; 29(10):903-7. DOI: 10.3109/00365529409094861. View

10.

Kanaseki T, Ikeda H, Takamura Y, Toyota M, Hirohashi Y, Tokino T . Histone deacetylation, but not hypermethylation, modifies class II transactivator and MHC class II gene expression in squamous cell carcinomas. J Immunol. 2003; 170(10):4980-5. DOI: 10.4049/jimmunol.170.10.4980. View

11.

Satoh A, Toyota M, Ikeda H, Morimoto Y, Akino K, Mita H . Epigenetic inactivation of class II transactivator (CIITA) is associated with the absence of interferon-gamma-induced HLA-DR expression in colorectal and gastric cancer cells. Oncogene. 2004; 23(55):8876-86. DOI: 10.1038/sj.onc.1208144. View

12.

Muto T, Kotake K, Koyama Y . Colorectal cancer statistics in Japan: data from JSCCR registration, 1974-1993. Int J Clin Oncol. 2001; 6(4):171-6. DOI: 10.1007/pl00012102. View

13.

Zeh H, Choti M . Vaccines for colorectal cancer. Trends Mol Med. 2001; 7(7):307-13. DOI: 10.1016/s1471-4914(01)01992-x. View

14.

Murphy S, Choi J, Holtz R . Regulation of major histocompatibility complex class II gene expression in trophoblast cells. Reprod Biol Endocrinol. 2004; 2:52. PMC: 479700. DOI: 10.1186/1477-7827-2-52. View

15.

Zhang L, Conejo-Garcia J, Katsaros D, Gimotty P, Massobrio M, Regnani G . Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003; 348(3):203-13. DOI: 10.1056/NEJMoa020177. View

16.

Dunn G, Bruce A, Ikeda H, Old L, Schreiber R . Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002; 3(11):991-8. DOI: 10.1038/ni1102-991. View

17.

Cherwinski H, Schumacher J, Brown K, Mosmann T . Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med. 1987; 166(5):1229-44. PMC: 2189643. DOI: 10.1084/jem.166.5.1229. View

18.

Sato K, Miyahara M, Saito T, Kobayashi M . c-myc mRNA overexpression is associated with lymph node metastasis in colorectal cancer. Eur J Cancer. 1994; 30A(8):1113-7. DOI: 10.1016/0959-8049(94)90468-5. View

19.

Armstrong T, Clements V, Ostrand-Rosenberg S . Class II-transfected tumor cells directly present endogenous antigen to CD4+ T cells in vitro and are APCs for tumor-encoded antigens in vivo. J Immunother. 1998; 21(3):218-24. DOI: 10.1097/00002371-199805000-00008. View

20.

Matsushita K, Takenouchi T, Kobayashi S, Hayashi H, Okuyama K, Ochiai T . HLA-DR antigen expression in colorectal carcinomas: influence of expression by IFN-gamma in situ and its association with tumour progression. Br J Cancer. 1996; 73(5):644-8. PMC: 2074349. DOI: 10.1038/bjc.1996.112. View