title: Activation of vitamin D receptor signaling downregulates the expression of nuclear FOXM1 protein and suppresses pancreatic cancer cell stemness.
abstract: OBJECTIVE
  Dysregulated signaling of nuclear transcription factors vitamin D receptor (VDR) and Forkhead box M1 (FOXM1) plays important roles in transformation and tumorigenesis. In this study, we sought to determine whether VDR signaling causally affected FOXM1 signaling in and pathogenesis of pancreatic ductal adenocarcinoma (PDAC).
  
  
  METHODS
  Genetic and pharmacologic approaches were used to manipulate VDR signaling. The impacts of altered VDR signaling on FOXM1 expression and function in PDAC cells were determined using molecular and biochemical methods, whereas those on PDAC cell biology and tumorigenicity were determined using in vitro and in vivo experimental systems. The clinical relevance of our findings was validated by analyzing human PDAC specimens.
  
  
  RESULTS
  There was a striking inverse correlation between reduced expression of VDR and increased expression of FOXM1 in human PDAC cells and tissues. Treatment of PDAC cells with 1,25-dihydroxyvitamin D3 (1,25D), its synthetic analogue EB1089 (EB), and VDR transgenics drastically inhibited FOXM1 signaling and markedly suppressed tumor stemness, growth, and metastasis. Mechanistically, 1,25D and EB repressed FOXM1 transcription and reduced the expression level of nuclear FOXM1 protein.
  
  
  CONCLUSIONS
  Inactivation of Vitamin D/VDR signaling is a critical contributor to PDAC development and progression via elevated expression and function of FOXM1 and enhanced PDAC cell stemness, invasion, and metastasis.
authors.affiliation: Department of Gastrointestinal Oncology, The Harbin Medical University Cancer Hospital, Harbin, People's Republic of China. Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
authors.forename: Dacheng
authors.initials: D
authors.lastname: Xie
authors.affiliation: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Daoyan
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
authors.forename: Jiujie
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lopa
authors.initials: L
authors.lastname: Mishra
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Suyun
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Gastrointestinal Oncology, The Harbin Medical University Cancer Hospital, Harbin, People's Republic of China. kepxie@mdanderson.org yanqiaozhang@126.com.
authors.forename: Yanqiao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas. kepxie@mdanderson.org yanqiaozhang@126.com.
authors.forename: Keping
authors.initials: K
authors.lastname: Xie
mesh_terms: D000818:Animals; D041702:BALB 3T3 Cells; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D005434:Flow Cytometry; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D046888:Tissue Array Analysis; D014162:Transfection
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol