title: Mesothelin (MSLN) promoter is hypomethylated in malignant mesothelioma, but its expression is not associated with methylation status of the promoter.
abstract: Gene methylation leads to malignant progression in some tumors. The mechanism by which mesothelin is expressed in malignant mesothelioma (MM) is not well understood. MM is histologically divided into 3 subtypes, that is, the epithelioid, sarcomatoid, and biphasic types, and it was shown that mesothelin expression was restricted to the epithelioid type and the epithelioid component of the biphasic type of MM. However, its regulatory mechanism of expression has not been clarified. Here, we studied the expression of mesothelin by immunohistochemistry along with the methylation status of 20 CpG sites in the promoter of the mesothelin gene (MSLN) in 118 lung specimens, including 39 MM, 41 lung carcinoma, 26 nonneoplastic pulmonary lesions, and 12 normal lung tissue samples by the methylation-sensitive single nucleotide primer extension technique. We confirmed that mesothelin was expressed in the epithelioid type and epithelioid component of the biphasic type of MM but neither in the sarcomatoid type nor sarcomatous component of the biphasic type. Surprisingly, the MSLN promoter was significantly hypomethylated in the MM cases regardless of its subtype, compared with the other pulmonary lesions and normal lung tissue samples. These findings suggested that hypomethylation of the MSLN promoter may be specifically associated with the formation of MM, regardless of its expression status, and that the expression of mesothelin protein was lost in the sarcomatoid type by some unknown posttranscriptional regulatory mechanism. We also identified 4 CpG sites, among the 20 sites studied, to be more specifically hypomethylated in MM cases.
authors.affiliation: Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Ke
authors.initials: K
authors.lastname: Tan
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kajino
authors.forename: Shuji
authors.initials: S
authors.lastname: Momose
authors.forename: Akiko
authors.initials: A
authors.lastname: Masaoka
authors.forename: Keiichi
authors.initials: K
authors.lastname: Sasahara
authors.forename: Kazu
authors.initials: K
authors.lastname: Shiomi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Izumi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Abe
authors.forename: Naomi
authors.initials: N
authors.lastname: Ohtsuji
authors.forename: Tegexibaiyin
authors.initials: T
authors.lastname: Wang
authors.forename: Okio
authors.initials: O
authors.lastname: Hino
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Fujii
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000032:analysis; D015622:Epithelioid Cells / Q000378:metabolism / Q000473:pathology; D058851:GPI-Linked Proteins; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D000090204:Mesothelin; D008654:Mesothelioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D010997:Pleural Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D004273:DNA, Neoplasm; D058851:GPI-Linked Proteins; C000715527:MSLN protein, human; D008562:Membrane Glycoproteins; D000090204:Mesothelin