title: Methionine-enkephalin secreted by human colorectal cancer cells suppresses T lymphocytes.
abstract: The role of methionine-enkephalin (MENK) as an immunomodulator in colorectal carcinomas (CRC) was examined. MENK was produced in CT26, IEC6A, Colo320, and HT29 CRC cell lines but not in IEC6 intestinal cells. MENK secretion was associated with tumorigenicity and metastasis of CRC cells in syngeneic rodent models. The MENK concentration in subcutaneous tumors of CT26 and IEC6A CRC cells exhibited an inverse correlation with the number of tumor-infiltrating T lymphocytes. MENK inhibited the growth of MOLT-4 T-lymphoblastic cells in a dose-dependent manner. Furthermore, it increased the phosphorylation level of c-Jun N-terminal kinase and induced apoptosis in MOLT-4 cells. MENK-induced apoptosis was abrogated by a c-Jun N-terminal kinase inhibitor. Immunohistochemical analysis revealed moderate to strong expression of MENK in 33 (54%) of 61 CRC. MENK expression was associated with Dukes' staging, nodal metastasis, and liver metastasis. The MENK concentration in tumor tissues was higher in Dukes' C cases than in Dukes' B cases. MENK expression was associated with tumor-infiltrating T lymphocytes, especially those belonging to the CD4(+) subset. These findings suggest that MENK secreted by CRC cells caused escape of the host from the effects of immunity.
authors.affiliation: Department of Molecular Pathology, Nara Medical University, Kashihara, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ohmori
authors.forename: Kiyomu
authors.initials: K
authors.lastname: Fujii
authors.forename: Tomonori
authors.initials: T
authors.lastname: Sasahira
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Mamoru
authors.initials: M
authors.lastname: Isobe
authors.forename: Naokuni
authors.initials: N
authors.lastname: Tatsumoto
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kuniyasu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000276:immunology*; D004744:Enkephalin, Methionine / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D004744:Enkephalin, Methionine; D020928:Mitogen-Activated Protein Kinases