title: NTRK3 is a potential tumor suppressor gene commonly inactivated by epigenetic mechanisms in colorectal cancer.
abstract: NTRK3 is a member of the neurotrophin receptor family and regulates cell survival. It appears to be a dependence receptor, and thus has the potential to act as an oncogene or as a tumor suppressor gene. NTRK3 is a receptor for NT-3 and when bound to NT-3 it induces cell survival, but when NT-3 free, it induces apoptosis. We identified aberrantly methylated NTRK3 in colorectal cancers through a genome-wide screen for hypermethylated genes. This discovery led us to assess whether NTRK3 could be a tumor suppressor gene in the colon. NTRK3 is methylated in 60% of colon adenomas and 67% of colon adenocarcinomas. NTRK3 methylation suppresses NTRK3 expression. Reconstitution of NTRK3 induces apoptosis in colorectal cancers, if NT-3 is absent. Furthermore, the loss of NTRK3 expression associates with neoplastic transformation in vitro and in vivo. We also found that a naturally occurring mutant NTRK3 found in human colorectal cancer inhibits the tumor suppressor activity of NTRK3. In summary, our findings suggest NTRK3 is a conditional tumor suppressor gene that is commonly inactivated in colorectal cancer by both epigenetic and genetic mechanisms whose function in the pathogenesis of colorectal cancer depends on the expression status of its ligand, NT-3.
authors.affiliation: Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Luo
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Kaz
authors.forename: Samornmas
authors.initials: S
authors.lastname: Kanngurn
authors.forename: Piri
authors.initials: P
authors.lastname: Welsch
authors.forename: Shelli M
authors.initials: SM
authors.lastname: Morris
authors.forename: Jianping
authors.initials: J
authors.lastname: Wang
authors.forename: James D
authors.initials: JD
authors.lastname: Lutterbaugh
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
authors.forename: William M
authors.initials: WM
authors.lastname: Grady
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D063185:Epigenetic Repression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D015894:Genome, Human; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011134:Polysaccharides / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020812:Receptor, trkC / Q000235:genetics*
chemical_list: D011134:Polysaccharides; C010491:neurotropin; D020812:Receptor, trkC