title: PAX3 is a novel tumor suppressor by regulating the activities of major signaling pathways and transcription factor FOXO3a in thyroid cancer.
abstract: Paired box 3 (PAX3) is expressed early during embryonic development in spatially restricted domains in the nervous system and in some mesodermally-derived structure. In recent years, it is found to be overexpressed in different types of cancer tissues and cell lines including glioblastomas, neuroblastomas, melanomas, rhabdomyosarcomas, Ewing sarcomas and gastric cancers, suggesting that it may function as an oncogene in these cancers. However, its role in thyroid cancer remains totally unclear. The aim of this study was to explore the functions and related molecular mechanism of PAX3 in thyroid tumorigenesis. Using quantitative RT-PCR (qRT-PCR) and Methylation-specific PCR (MSP) assays, we demonstrated that PAX3 was frequently down-regulated by promoter methylation in both primary thyroid cancer tissues and thyroid cancer cell lines. In addition, our data showed that ectopic expression of PAX3 dramatically inhibited thyroid cancer cell proliferation, colony formation, migration and invasion, induced cell cycle arrest and apoptosis and retarded tumorigenic potential in nude mice. Mechanically, PAX3 exerted its tumor suppressor function by inhibiting the activity of major signaling pathways including the phosphatidylinositol-3-kinase (PI3K)/Akt and MAPK/Erk pathways, and enhancing expression and activity of transcription factor FOXO3a. Altogether, our findings provided insight into the role of PAX3 as a novel functional tumor suppressor in thyroid cancer through modulating the activities of PI3K/Akt and MAPK signaling pathways and transcription factor FOXO3a, and demonstrated that epigenetic alterations such as promoter methylation should be a major mechanism of PAX3 inactivation in this cancer.
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Sui
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
authors.forename: Jiazhe
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
authors.forename: Meichen
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
authors.forename: Sijia
authors.initials: S
authors.lastname: Tian
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
authors.forename: Meiju
authors.initials: M
authors.lastname: Ji
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.|Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
authors.forename: Bingyin
authors.initials: B
authors.lastname: Shi
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.|Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Hou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D008819:Mice, Nude; D000072041:PAX3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D025521:Tumor Suppressor Proteins
keywords: FOXO3a; MAPK/Erk pathway; PAX3; PI3K/Akt pathway; thyroid cancer