title: Differential roles of RET isoforms in medullary and papillary thyroid carcinomas.
abstract: The RET receptor tyrosine kinase mediates cell proliferation, survival and migration in embryogenesis and is implicated in the transformation and tumour progression in multiple cancers. RET is frequently mutated and constitutively activated in familial and sporadic thyroid carcinomas. As a result of alternative splicing, RET is expressed as two protein isoforms, RET9 and RET51, which differ in their unique C-terminal amino acids. These isoforms have distinct intracellular trafficking and associated signalling complexes, but functional differences are not well defined. We used shRNA-mediated knockdown (KD) of individual RET isoforms or of total RET to evaluate their functional contributions in thyroid carcinoma cells. We showed that RET is required for cell survival in medullary (MTC) but not papillary thyroid carcinoma (PTC) cells. In PTC cells, RET depletion reduced cell migration and induced a flattened epithelial-like morphology. RET KD decreased the expression of mesenchymal markers and matrix metalloproteinases and reduced anoikis resistance and invasive potential. Further, we showed that RET51 depletion had significantly greater effects on each of these processes than RET9 depletion in both MTC and PTC cells. Finally, we showed that expression of RET, particularly RET51, was correlated with malignancy in a panel of human thyroid tumour tissues. Together, our data show that RET expression promotes a more mesenchymal phenotype with reduced cell-cell adhesion and increased invasiveness in PTC cell models, but is more important for tumour cell survival, proliferation and anoikis resistance in MTC models. Our data suggest that the RET51 isoform plays a more prominent role in mediating these processes compared to RET9.
authors.affiliation: Division of Cancer Biology and GeneticsCancer Research Institute, Queen's University, Kingston, Ontario, Canada.|Department of Pathology & Molecular MedicineQueen's University, Kingston, Ontario, Canada.
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Lian
authors.affiliation: Division of Cancer Biology and GeneticsCancer Research Institute, Queen's University, Kingston, Ontario, Canada.|Department of Pathology & Molecular MedicineQueen's University, Kingston, Ontario, Canada.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Maritan
authors.affiliation: Division of Cancer Biology and GeneticsCancer Research Institute, Queen's University, Kingston, Ontario, Canada.|Department of Pathology & Molecular MedicineQueen's University, Kingston, Ontario, Canada.
authors.forename: Jessica G
authors.initials: JG
authors.lastname: Cockburn
authors.affiliation: Michael Smith Genome Sciences CentreBritish Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Katayoon
authors.initials: K
authors.lastname: Kasaian
authors.affiliation: Division of Cancer Biology and GeneticsCancer Research Institute, Queen's University, Kingston, Ontario, Canada.|Department of Pathology & Molecular MedicineQueen's University, Kingston, Ontario, Canada.
authors.forename: Mathieu J F
authors.initials: MJ
authors.lastname: Crupi
authors.affiliation: Department of Pathology & Molecular MedicineQueen's University, Kingston, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Hurlbut
authors.affiliation: Michael Smith Genome Sciences CentreBritish Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.|Department of Medical GeneticsUniversity of British Columbia, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Steven J M
authors.initials: SJ
authors.lastname: Jones
authors.affiliation: Department of SurgerySt Paul's Hospital & University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sam M
authors.initials: SM
authors.lastname: Wiseman
authors.affiliation: Division of Cancer Biology and GeneticsCancer Research Institute, Queen's University, Kingston, Ontario, Canada mulligal@queensu.ca.|Department of Pathology & Molecular MedicineQueen's University, Kingston, Ontario, Canada.
authors.forename: Lois M
authors.initials: LM
authors.lastname: Mulligan
mesh_terms: D018278:Carcinoma, Neuroendocrine / Q000235:genetics / Q000378:metabolism*; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D034741:RNA, Small Interfering; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
keywords: RET isoforms; epithelial–mesenchymal transition; invasion; migration; thyroid carcinoma