title: SOSTDC1 down-regulation of expression involves CpG methylation and is a potential prognostic marker in gastric cancer.
abstract: Sclerostin domain containing 1 (SOSTDC1) is reportedly down-regulated in various cancers. Our purpose was to study whether epigenetic mechanisms were involved in the down-regulation of expression in gastric cancer. Expression analysis of SOSTDC1 in gastric cancer cell lines indicated mRNA down-regulation. Our reporter assays and gene reactivation studies using 5-aza-2'-deoxycytidine, a DNA demethylating agent, and trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, demonstrated that epigenetic mechanisms are involved in the down-regulation of SOSTC1 expression. Methylation analysis of the SOSTDC1 promoter CpGs using methylation-specific polymerase chain reaction analysis revealed methylation in gastric cancer cell lines and tissue samples. A majority of tumors (17 of 18) with observed methylation exhibited down-regulation of mRNA expression relative to apparently normal gastric tissues. Immunoreactivity for SOSTDC1 in gastric tumors (24 of 46, 52.1%) was down-regulated relative to normal tissues (36 of 38, 94.7%) (P = 0.00001). The difference in expression between gastric tumor subtypes, intestinal and diffuse, was significant (P = 0.040). Expression of SOSTDC1 in gastric tumors increased the probability of both overall and disease-free survival. When overexpressed in AGS cells, cell proliferation, cell cycle progression, and anchorage-independent growth was repressed. The present findings indicate SOSTDC1 down-regulation involves methylation; SOSTDC1 expression is a potential prognostic factor and tumor suppressor in gastric cancer.
authors.affiliation: Department of Molecular Oncology, Cancer Institute (Women's India Association), Chennai, India.
authors.forename: Gopisetty
authors.initials: G
authors.lastname: Gopal
authors.forename: Uthandaraman Mahalinga
authors.initials: UM
authors.lastname: Raja
authors.forename: Sundersingh
authors.initials: S
authors.lastname: Shirley
authors.forename: Kamlalyam Raghavan
authors.initials: KR
authors.lastname: Rajalekshmi
authors.forename: Thangarajan
authors.initials: T
authors.lastname: Rajkumar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001483:Base Sequence; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D015536:Down-Regulation; D005819:Genetic Markers; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; C480733:SOSTDC1 protein, human
keywords: SOSTDC1; epigenetics; gastric cancer; prognosis; promoter methylation