title: Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma.
abstract: Secreted frizzled-related proteins (sFRPs) comprise a family of five secreted glycoproteins that antagonize Wnt signaling. Aberrant activation and upregulation of the Wnt pathway is a key feature of many cancers. Thus, role of sFRP as a negative regulator of Wnt signaling may have important implications in tumorigenesis, and its downregulation has been correlated with human cancers. Recently, we reported Wnt signaling and dishevelled (Dvl) overexpression in malignant pleural mesothelioma (MM). Here, we report significant transcriptional downregulation of the SFRP gene family in MM primary tissues and cell lines as well as several other cancer cell lines (breast, lung, glioma, and cervical) compared to normal cells. One or more SFRPs were downregulated in approximately 85% (18 of 21) of primary MM tumor specimens compared to normal pleural tissue. Eight of the nine cancer cell lines we examined showed silencing of the SFRP family. Methylation-specific PCR (MSP) analysis showed that SFRP1, SFRP4, and SFRP5 gene promoters are frequently methylated in MM primary tissue (>80%). Furthermore, transfection of the SFRP gene construct into MM cell lines lacking SFRP expression resulted in apoptosis and growth suppression. Our results suggest that methylation silencing of SFRPs may be one of the important mechanisms of aberrant Wnt signaling activation in MM.
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA.
authors.forename: Amie Y
authors.initials: AY
authors.lastname: Lee
authors.forename: Biao
authors.initials: B
authors.lastname: He
authors.forename: Liang
authors.initials: L
authors.lastname: You
authors.forename: Sina
authors.initials: S
authors.lastname: Dadfarmay
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Xu
authors.forename: Julien
authors.initials: J
authors.lastname: Mazieres
authors.forename: Iwao
authors.initials: I
authors.lastname: Mikami
authors.forename: Frank
authors.initials: F
authors.lastname: McCormick
authors.forename: David M
authors.initials: DM
authors.lastname: Jablons
mesh_terms: D015536:Down-Regulation; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D010997:Pleural Neoplasms / Q000235:genetics* / Q000473:pathology; D000099274:Frizzled-Related Proteins
chemical_list: D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D000099274:Frizzled-Related Proteins