title: Vitamin D Deficiency Promotes Liver Tumor Growth in Transforming Growth Factor-β/Smad3-Deficient Mice Through Wnt and Toll-like Receptor 7 Pathway Modulation.
abstract: Disruption of the TGF-β pathway is associated with liver fibrosis and suppression of liver tumorigenesis, conditions associated with low Vitamin D (VD) levels. However, potential contributions of VD to liver tumor progression in the context of TGF-β signaling remain unexplored. Our analyses of VD deprivation (VDD) in in vivo models of liver tumor formation revealed striking three-fold increases in tumor burden in Smad3(+/-) mice, with a three-fold increase in TLR7 expression compared to controls. ChIP and transcriptional assays confirm Smad3 binding at two TLR7 promoter SBE sites. Molecular interactions between TGF-β pathway and VDD were validated clinically, where an absence of VD supplementation was associated with low TGF-β pathway member expression levels and β-catenin activation in fibrotic/cirrhotic human liver tissues. Subsequent supplementing VD led to restoration of TGF-β member expression with lower β-catenin levels. Bioinformatics analysis provides positive supportive correlation between somatic mutations for VD-related genes and the TGF-β pathway. We conclude that VDD promotes tumor growth in the context of Smad3 disruption, potentially through regulation of TLR7 expression and β-catenin activation. VD could therefore be a strong candidate for liver cancer prevention in the context of aberrant Smad3 signaling.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Department of Gastroenterology, Hepatology, and Nutrition, Houston, TX 77030, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: The University of Texas MD Anderson Cancer Center, Department of Gastroenterology, Hepatology, and Nutrition, Houston, TX 77030, USA.|Sheba Medical Center, Department of Gastroenterology, Tel Hashomer, 52621, Israel.
authors.forename: Lior H
authors.initials: LH
authors.lastname: Katz
authors.affiliation: The University of Texas MD Anderson Cancer Center, Department of Gastroenterology, Hepatology, and Nutrition, Houston, TX 77030, USA.
authors.forename: Nina M
authors.initials: NM
authors.lastname: Muñoz
authors.affiliation: George Washington University, Department of Surgery, Washington, DC, 20052, USA.
authors.forename: Shoujun
authors.initials: S
authors.lastname: Gu
authors.affiliation: The University of Texas MD Anderson Cancer Center, Department of Gastroenterology, Hepatology, and Nutrition, Houston, TX 77030, USA.
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC, 20422, USA.
authors.forename: Wilma S
authors.initials: WS
authors.lastname: Jogunoori
authors.affiliation: Georgetown University, Department of Molecular Oncology, Washington, DC, 20057, USA.
authors.forename: Mi-Hye
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC, 20422, USA.
authors.forename: Mitchell D
authors.initials: MD
authors.lastname: Belkin
authors.affiliation: The University of Texas MD Anderson Cancer Center, Department of Systems Biology, Houston, TX, 77030, USA.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC, 20422, USA.
authors.forename: Jon C
authors.initials: JC
authors.lastname: White
authors.affiliation: George Washington University, Department of Anatomy and Regenerative Biology, Washington, DC, 20052, USA.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Andricovich
authors.affiliation: George Washington University, Department of Anatomy and Regenerative Biology, Washington, DC, 20052, USA.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Tzatsos
authors.affiliation: The University of Texas MD Anderson Cancer Center, Department of Pediatrics, Houston, TX, 77030, USA.
authors.forename: Shulin
authors.initials: S
authors.lastname: Li
authors.affiliation: National Cancer Center, Radiation Medicine Branch, Goyang, 410-769, Korea.
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kim
authors.affiliation: Johns Hopkins University, School of Medicine, Baltimore, MD, 21287, USA.
authors.forename: Kirti
authors.initials: K
authors.lastname: Shetty
authors.affiliation: Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC, 20422, USA.
authors.forename: Bibhuti
authors.initials: B
authors.lastname: Mishra
authors.affiliation: The University of Texas MD Anderson Cancer Center, Department of Pathology, Houston, TX, 77030, USA.
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.affiliation: The University of Texas MD Anderson Cancer Center, Department of Systems Biology, Houston, TX, 77030, USA.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: The University of Texas MD Anderson Cancer Center, Department of Gastroenterology, Hepatology, and Nutrition, Houston, TX 77030, USA.|George Washington University, Department of Surgery, Washington, DC, 20052, USA.|Center for Translational Medicine, Department of Surgery and George Washington Cancer Center, George Washington University, Washington, DC, USA.
authors.forename: Lopa
authors.initials: L
authors.lastname: Mishra
mesh_terms: D000818:Animals; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000150:complications / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics*; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics*; D014807:Vitamin D / Q000008:administration & dosage; D014808:Vitamin D Deficiency / Q000150:complications*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D014807:Vitamin D