Abstract
Cancer cells that survive fractionated irradiation can be radioresistant and cause tumor recurrence. However, the molecular mechanisms underlying the development of radioresistance in cancer cells remain elusive. The aim of this study was to investigate the role of WISP-1 in the development of radioresistance in esophageal carcinoma during fractionated irradiation. Radioresistant esophageal cancer cells were generated from normal esophageal cancer cells via fractionated irradiation, and expression levels of related proteins were determined by Western blot. Radiosensitivity of cells was established by clonogenic cell survival assays, and cell cycle distribution was evaluated by flow cytometry. Protein distributions were determined by immunofluorescence, and cell toxicity was evaluated by cell counting kit-8 assays. In vivo validations were performed in a xenograft transplantation mouse model. Our data indicate that WISP-1 plays an important role in the development of radioresistance in esophageal cancer cells during fractionated irradiation. The overexression of WISP-1 in esophageal cancer cells was associated with radioresistance. Depletion of extracellular WISP-1 by antibody neutralizing reversed radioresistance and directly induced mitotic catastrophe resulting in cell death. WISP-1 may be a candidate therapeutic target in the treatment of recurrent esophageal carcinoma after radiotherapy.
Highlights
Esophageal carcinoma is a relatively rare form of cancer, but it is one of the most lethal malignancies worldwide
Zhang et al recently showed that radioresistant esophageal cancer cells can be established by repeated fractionated irradiation (FIR; the total dose of radiation is spread among fractions and delivered over time), and indicated that b-catenin might play an important role in the development of radioresistance during FIR [4]
To explore the molecular mechanisms involved in radioresistance, radioresistant esophageal cancer cell lines were established by applying repeated 2-Gy FIR using methodology described by Zhang et al [4]
Summary
Esophageal carcinoma is a relatively rare form of cancer, but it is one of the most lethal malignancies worldwide. The Wnt/b-catenin pathway can be aberrantly activated by irradiation exposure, resulting in the accumulation of b-catenin in the cytoplasm, its subsequent translocation into the nucleus, and the transcription of b-catenin target genes [5]. This aberrant activation of the Wnt/b-catenin pathway has been implicated in radioresistance of solid tumors such as glioblastoma [6], breast cancer [7], and head and neck cancer [4]. The mechanism by which the Wnt pathway contributes to radioresistance is unclear
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