title: 1α,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling.
abstract: The aim of this study was to highlight the role of 1α,25-dihydroxyvitamin D3 (calcitriol) in esophageal squamous cell carcinoma (SCC). The human esophageal SCC cell lines CE81T and TE2 were selected for cellular and animal experiments to investigate the changes in tumor behavior after calcitriol supplementation and the underlying mechanisms. Moreover, we evaluated the relationship between calcitriol supplementation, myeloid-derived suppressor cell (MDSC) recruitment, IL6 levels, and tumor progression by a 4-nitroquinoline 1-oxide (4-NQO)-induced esophageal tumor animal model. In this study, we demonstrated that calcitriol supplementation inhibited aggressive tumor behavior both in vitro and in vivo. The underlying changes included increased cell death, a lower degree of epithelial-mesenchymal transition, and inhibited IL6 signaling. In the 4-NQO-induced esophageal tumor animal model, increased IL6 and MDSC recruitment were linked with invasive esophageal tumors. Supplementation with calcitriol attenuated the level of IL6, the induction of MDSCs, and the incidence of 4-NQO-induced invasive tumors. Moreover, the IL6-induced changes in C57 mice, including augmented MDSC recruitment, increased levels of ROS and p-Stat3 in MDSCs, and higher suppressive function of MDSCs in T-cell proliferation, which were abrogated by calcitriol supplementation. On the basis of our results, we concluded that calcitriol abrogated the IL6-induced aggressive tumor behavior and MDSC recruitment to inhibit esophageal tumor promotion. Therefore, we suggest that supplementation with vitamin D3 may be a promising strategy for the prevention and treatment of esophageal SCC.
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Department of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Ping-Tsung
authors.initials: PT
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. General Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Ching-Chuan
authors.initials: CC
authors.lastname: Hsieh
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan. Department of Urology, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Chun-Te
authors.initials: CT
authors.lastname: Wu
authors.affiliation: Nuclear Medicine Department, Chang Gung Memorial Hospital at Linkou, Linkou, Taiwan. Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital at Linkou, Linkou, Taiwan.
authors.forename: Tzu-Chen
authors.initials: TC
authors.lastname: Yen
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Paul-Yang
authors.initials: PY
authors.lastname: Lin
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan. Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Chen
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan. Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan. miaofen@adm.cgmh.org.tw.
authors.forename: Miao-Fen
authors.initials: MF
authors.lastname: Chen
mesh_terms: D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D015363:Quinolones; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D047368:Tumor Burden / Q000187:drug effects; D014815:Vitamins / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C120195:4-nitroquinolone-1-oxide; D015850:Interleukin-6; D015363:Quinolones; D050796:STAT3 Transcription Factor; D014815:Vitamins; D015112:4-Nitroquinoline-1-oxide; D002117:Calcitriol