MAL gene expression in esophageal cancer suppresses motility, invasion and tumorigenicity and enhances apoptosis through the Fas pathway.
We isolated the MAL (T-lymphocyte maturation associated protein) gene from differentially expressed products of esophageal epithelium relative to esophageal carcinoma tissues. The Mal protein has been demonstrated as being a component of the protein machinery for apical transport in epithelial polarized cells. In this study, we describe the reduced expression of MAL in all 39 cases of esophageal carcinoma tested and 60 other human carcinomas. MAL gene transcription was induced in three out of 13 esophageal carcinoma cell lines by treatment with the demethylating agent 5-aza-2'-deoxycytidine (DAC), and in nine additional cell lines by simultaneous treatment with trichostatin A, an inhibitor of deacetylation, and DAC. We established a stable MAL gene transfectant whose expression was regulated by subcutaneous doxycycline injection in nude mice. Tumor growth was suppressed in cells expressing TE3-MAL compared with TE3 parent cells or cells not expressing TE3-MAL with doxycycline injection (20 microg/body) (P<0.01). Additionally, the TE3-MAL transfectant cells exhibited decreased cellular motility, a G1/S transition block and increased levels of apoptosis, concomitant with increased expression of Fas receptor in vitro. The apoptotic staining in MAL-expressing tumors was confirmed by TUNEL assay. Therefore, we conclude that expression of MAL was frequently decreased or diminished in gastrointestinal tract cancers, and that Mal expression confers reduced tumorigenicity in vivo to tumor TE3 cells through the induction of apoptosis via the Fas signaling pathway.
Mimori
Koshi
K
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu 874-0838, Japan.
Shiraishi
Takeshi
T
Mashino
Kohjiro
K
Sonoda
Hideto
H
Yamashita
Keishi
K
Yoshinaga
Keiji
K
Masuda
Takaaki
T
Utsunomiya
Tohru
T
Alonso
Miguel A
MA
Inoue
Hiroshi
H
Mori
Masaki
M
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D026901:Membrane Transport Proteins; D051379:Mice; D008819:Mice, Nude; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D009361:Neoplasm Invasiveness / Q000235:genetics; D011510:Proteolipids / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism
C569026:MAL protein, human; C569027:Mal protein, mouse; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D011510:Proteolipids; D019014:fas Receptor