title: Fractionated Ionizing Radiation Promotes Epithelial-Mesenchymal Transition in Human Esophageal Cancer Cells through PTEN Deficiency-Mediated Akt Activation.
abstract: In some esophageal cancer patients, radiotherapy may not prevent distant metastasis thus resulting in poor survival. The underlying mechanism of metastasis in these patients is not well established. In this study, we have demonstrated that ionizing radiation may induce epithelial-mesenchymal transition (EMT) accompanied with increased cell migration and invasion, through downregulation of phosphatase and tensin homolog (PTEN), and activation of Akt/GSK-3β/Snail signaling. We developed a radioresistant (RR) esophageal squamous cancer cell line, KYSE-150/RR, by fractionated ionizing radiation (IR) treatment, and confirmed its radioresistance using a clonogenic survival assay. We found that the KYSE-150/RR cell line displayed typical morphological and molecular characteristics of EMT. In comparison to the parental cells, KYSE-150/RR cells showed an increase in post-IR colony survival, migration, and invasiveness. Furthermore, a decrease in PTEN in KYSE-150/RR cells was observed. We postulated that over-expression of PTEN may induce mesenchymal-epithelial transition in KYSE-150/RR cells and restore IR-induced increase of cell migration. Mechanistically, fractionated IR inhibits expression of PTEN, which leads to activation of Akt/GSK-3β signaling and is associated with the elevated levels of Snail protein, a transcription factor involved in EMT. Correspondingly, treatment with LY294002, a phosphatidylinositol-3-kinase inhibitor, mimicked PTEN overexpression effect in KYSE-150/RR cells, further suggesting a role for the Akt/GSK-3β/Snail signaling in effects mediated through PTEN. Together, these results strongly suggest that fractionated IR-mediated EMT in KYSE-150/RR cells is through PTEN-dependent pathways, highlighting a direct proinvasive effect of radiation treatment on tumor cells.
authors.affiliation: Nankai University School of Medicine, Tianjin, China; Chinese PLA General Hospital and Chinese PLA Medical School, Beijing, China; Beijing Friendship Hospital, affiliated with Capital Medical University, Beijing, China.
authors.forename: Enhui
authors.initials: E
authors.lastname: He
authors.affiliation: Nankai University School of Medicine, Tianjin, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Pan
authors.affiliation: School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, Guangdong, China.
authors.forename: Guangchao
authors.initials: G
authors.lastname: Li
authors.affiliation: Chinese PLA General Hospital and Chinese PLA Medical School, Beijing, China; Beijing Friendship Hospital, affiliated with Capital Medical University, Beijing, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000528:radiation effects; D015536:Down-Regulation / Q000528:radiation effects; D058750:Epithelial-Mesenchymal Transition / Q000528:radiation effects*; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects*
chemical_list: C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase