title: PTK7 regulates radioresistance through nuclear factor-kappa B in esophageal squamous cell carcinoma.
abstract: Tumor radioresistance is a major reason for decreased efficiency of cancer radiation therapy. Although a number of factors involved in radioresistance have been identified, the molecular mechanisms underlying radioresistance of esophageal squamous cell carcinoma (ESCC) have not been elucidated. In this study, we investigated the role of oncogenic protein tyrosine kinase 7 (PTK7) in the resistance of ESCC to radiation therapy. ESCC cell lines with high PTK7 expression were more refractive to radiation than those with low PTK7 levels. In radioresistant ESCC cells, PTK7 knockdown by specific siRNAs decreased the survival of irradiated cells and increased radiation-induced apoptosis, while in radiosensitive ESCC cells, PTK7 overexpression promoted cell survival and inhibited radiation-induced apoptosis. We hypothesized that PTK7 could regulate the activation of transcription factor NF-kB known for its role in cancer radioresistance. Our results indicated that the inhibition of PTK7 suppressed nuclear translocation of NF-kB subunit p65 induced by radiation, suggesting relevance of PTK7 expression with NF-kB activation in radioresistant ESCC. Furthermore, the levels of inhibitor of apoptosis proteins (IAPs), XIAP, and survivin, encoded by NF-kB-regulated genes, were induced in irradiated radioresistant cells but not in radiosensitive cells, while PTK7 knockdown downregulated IAP expression. Our findings revealed a novel mechanism underlying radioresistance in ESCC, which is associated with PTK7 and NF-kB-dependent apoptosis. These results suggest that the manipulation of PTK7 expression can be instrumental in enhancing ESCC response to radiotherapy. This study demonstrates that PTK7 plays a significant role in ESCC radioresistance via the NF-kB pathway.
authors.affiliation: Department of Translational Research, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, 139-706, South Korea.|Department of Radiological and Medico-Oncological Sciences, Korea University of Science and Technology, Daejeon, South Korea.
authors.forename: Misun
authors.initials: M
authors.lastname: Park
authors.affiliation: Department of Translational Research, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, 139-706, South Korea.
authors.forename: Hyeon-Joon
authors.initials: HJ
authors.lastname: Yoon
authors.affiliation: Department of Thoracic Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, 139-706, South Korea.
authors.forename: Moon Chul
authors.initials: MC
authors.lastname: Kang
authors.affiliation: Department of Translational Research, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, 139-706, South Korea. jhkwon@kirams.re.kr.
authors.forename: Junhye
authors.initials: J
authors.lastname: Kwon
authors.affiliation: Department of Thoracic Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, 139-706, South Korea. thorax@kirams.re.kr.
authors.forename: Hae Won
authors.initials: HW
authors.lastname: Lee
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D049109:Cell Proliferation / Q000528:radiation effects; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D005455:Fluorescent Antibody Technique; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011836:Radiation Tolerance; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D015815:Cell Adhesion Molecules; D016328:NF-kappa B; C096905:PTK7 protein, human; D020794:Receptor Protein-Tyrosine Kinases
keywords: Apoptosis; ESCC; NF-kB; PTK7; Radioresistance