title: Fractionated irradiation-induced EMT-like phenotype conferred radioresistance in esophageal squamous cell carcinoma.
abstract: The efficacy of radiotherapy, one major treatment modality for esophageal squamous cell carcinoma (ESCC) is severely attenuated by radioresistance. Epithelial-to-mesenchymal transition (EMT) is a cellular process that determines therapy response and tumor progression. However, whether EMT is induced by ionizing radiation and involved in tumor radioresistance has been less studied in ESCC. Using multiple fractionated irradiation, the radioresistant esophageal squamous cancer cell line KYSE-150R had been established from its parental cell line KYSE-150. We found KYSE-150R displayed a significant EMT phenotype with an elongated spindle shape and down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker N-cadherin in comparison with KYSE-150. Furthermore, KYSE-150R also possessed some stemness-like properties characterized by density-dependent growth promotion and strong capability for sphere formation and tumorigenesis in NOD-SCID mice. Mechanical studies have revealed that WISP1, a secreted matricellular protein, is highly expressed in KYSE-150R and mediates EMT-associated radioresistance both in ESCC cells and in xenograft tumor models. Moreover, WISP1 has been demonstrated to be closely associated with the EMT phenotype observed in ESCC patients and to be an independent prognosis factor of ESCC patients treated with radiotherapy. Our study highlighted WISP1 as an attractive target to reverse EMT-associated radioresistance in ESCC and can be used as an independent prognostic factor of patients treated with radiotherapy.
authors.affiliation: Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, 310002, China.
authors.forename: Hongfang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of radiotherapy, Huai'an First People's Hospital, Huai'an, 223300, China.
authors.forename: Honglei
authors.initials: H
authors.lastname: Luo
authors.affiliation: Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, 310002, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, 310002, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yue
authors.affiliation: Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, 310002, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hou
authors.affiliation: Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, 310002, China.
authors.forename: Ruifei
authors.initials: R
authors.lastname: Xie
authors.affiliation: Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, 310002, China wushixiu2014@163.com.
authors.forename: Shixiu
authors.initials: S
authors.lastname: Wu
mesh_terms: D000818:Animals; D055511:CCN Intercellular Signaling Proteins; D002294:Carcinoma, Squamous Cell / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D019583:Dose Fractionation, Radiation; D058750:Epithelial-Mesenchymal Transition / Q000528:radiation effects*; D004938:Esophageal Neoplasms / Q000532:radiotherapy*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D011518:Proto-Oncogene Proteins; D011836:Radiation Tolerance / Q000528:radiation effects*; D011839:Radiation, Ionizing; D023041:Xenograft Model Antitumor Assays
chemical_list: D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; D011518:Proto-Oncogene Proteins
keywords: EMT; ESCC; WISP1; prognosis significance; radioresistance