title: T-lymphocyte maturation-associated protein gene as a candidate metastasis suppressor for head and neck squamous cell carcinomas.
abstract: Previous gene expression profiles revealed the T-lymphocyte maturation-associated protein (MAL) gene as being frequently downregulated in head and neck cancer. To define the relationship between the MAL gene and the metastatic process, we evaluated the expression status of the gene in matched primary and metastatic tumors of head and neck cancer by semiquantitative reverse transcription-polymerase chain reaction. Furthermore, we aimed to identify potential genetic and epigenetic mechanisms associated with downregulation of MAL, including loss of heterozygosity (LOH), mutation, and hypermethylation. Thirty-five cell lines of University of Turko squamous cell carcinoma (UT-SCC) series derived from head and neck cancer, including nine pairs from matched primary and metastatic tumors, and 30 pairs of matched primary and metastatic tumor samples were analyzed. Twenty out of 35 (57%) cell lines showed downregulation of MAL expression, whereas no expression was found in 10 cell lines (29%). Considering matched primary and metastatic tumor-derived cell-line pairs, four pairs showed decreased expression only in metastasis-derived cells compared with their primary counterparts. Expression analysis of 21 tissue samples demonstrated decreased or no expression of MAL mRNA in 43% of metastatic tumors compared with matched primary tumors. Relating to mechanisms of downregulation, LOH was observed in 30% of primary tumors and 38% of their metastatic counterparts by a MAL-specific microsatellite marker. Furthermore, we found restoration of MAL mRNA after treatment with demethylating agent (5-aza-2'-deoxycytidine) in 9 (45%) out of 20 cell lines. No mutation was found in UT-SCC cell lines. In conclusion, our findings indicate selective downregulation of MAL expression in metastatic cells, suggesting the MAL gene as a new metastasis-suppressor candidate for head and neck cancer. LOH and hypermethylation appeared to be important mechanisms for inactivation of MAL function.
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan.
authors.forename: Levent Bekir
authors.initials: LB
authors.lastname: Beder
authors.forename: Mehmet
authors.initials: M
authors.lastname: Gunduz
authors.forename: Muneki
authors.initials: M
authors.lastname: Hotomi
authors.forename: Keiji
authors.initials: K
authors.lastname: Fujihara
authors.forename: Jun
authors.initials: J
authors.lastname: Shimada
authors.forename: Shinji
authors.initials: S
authors.lastname: Tamura
authors.forename: Esra
authors.initials: E
authors.lastname: Gunduz
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Fukushima
authors.forename: Kursat
authors.initials: K
authors.lastname: Yaykasli
authors.forename: Reidar
authors.initials: R
authors.lastname: Grenman
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimizu
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamanaka
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000077209:Decitabine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D011510:Proteolipids / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C569026:MAL protein, human; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D011510:Proteolipids; D012333:RNA, Messenger; D000077209:Decitabine; D001374:Azacitidine