title: Progeny from irradiated colorectal cancer cells acquire an EMT-like phenotype and activate Wnt/β-catenin pathway.
abstract: Radiotherapy remains a major approach to adjuvant therapy for patients with advanced colorectal cancer, however, the fractionation schedules frequently allow for the repopulation of surviving tumors cells, neoplastic progression, and subsequent metastasis. The aim of the present study was to analyze the transgenerational effects induced by radiation and evaluate whether it could increase the malignant features on the progeny derived from irradiated parental colorectal cancer cells, Caco-2, HT-29, and HCT-116. The progeny of these cells displayed a differential radioresistance as seen by clonogenic and caspase activation assay and had a direct correlation with survivin expression as observed by immunoblotting. Immunofluorescence showed that the most radioresistant progenies had an aberrant morphology, disturbance of the cell-cell adhesion contacts, disorganization of the actin cytoskeleton, and vimentin filaments. Only the progeny derived from intermediary radioresistant cells, HT-29, reduced the E-cadherin expression and overexpressed β-catenin and vimentin with increased cell migration, invasion, and metalloprotease activation as seen by immunoblotting, wound healing, invasion, and metalloprotease activity assay. We also observed that this most aggressive progeny increased the Wnt/β-catenin-dependent TCF/LEF activity and underwent an upregulation of mesenchymal markers and downregulation of E-cadherin, as determined by qRT-PCR. Our results showed that the intermediate radioresistant cells can generate more aggressive cellular progeny with the EMT-like phenotype. The Wnt/β-catenin pathway may constitute an important target for new adjuvant treatment schedules with radiotherapy, with the goal of reducing the migratory and invasive potential of the remaining cells after treatment.
authors.affiliation: Cellular Biology Program, Brazilian National Cancer Institute (INCA), 37André Cavalcanti Street, 5th Floor, Rio de Janeiro, RJ, 20230-051, Brazil.
authors.forename: Lilian Gonçalves dos Reis
authors.initials: LG
authors.lastname: Bastos
authors.forename: Priscila Guimarães
authors.initials: PG
authors.lastname: de Marcondes
authors.forename: Julio Cesar Madureira
authors.initials: JC
authors.lastname: de-Freitas-Junior
authors.forename: Fernanda
authors.initials: F
authors.lastname: Leve
authors.forename: André Luiz
authors.initials: AL
authors.lastname: Mencalha
authors.forename: Waldemir Fernandes
authors.initials: WF
authors.lastname: de Souza
authors.forename: Wallace Martins
authors.initials: WM
authors.lastname: de Araujo
authors.forename: Marcelo Neves
authors.initials: MN
authors.lastname: Tanaka
authors.forename: Eliana Saul Furquim Werneck
authors.initials: ES
authors.lastname: Abdelhay
authors.forename: José Andrés
authors.initials: JA
authors.lastname: Morgado-Díaz
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D015703:Antigens, CD; D017209:Apoptosis; D018938:Caco-2 Cells; D015820:Cadherins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002465:Cell Movement / Q000528:radiation effects*; D048430:Cell Shape; D015179:Colorectal Neoplasms; D058750:Epithelial-Mesenchymal Transition / Q000528:radiation effects*; D019073:HT29 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011836:Radiation Tolerance; D000077022:Survivin; D014746:Vimentin / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C107489:BIRC5 protein, human; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D014746:Vimentin; D051176:beta Catenin; D020169:Caspases
keywords: COLORECTAL CANCER; EMT; RADIORESISTANCE; Wnt/β-CATENIN PATHWAY