title: Hepatocellular carcinoma cells express 25(OH)D-1α-hydroxylase and are able to convert 25(OH)D to 1α,25(OH)₂D, leading to the 25(OH)D-induced growth inhibition.
abstract: Hepatocellular carcinoma (HCC) is the most diagnosed liver cancer without effective treatments available for advanced HCC. Vitamin D is getting popular due to its anti-cancer characteristics. However, the clinical application of 1α,25(OH)2D, the active form of vitamin, is hampered by its hypercalcemia side effect. 1α,25(OH)2D is converted from 25(OH)D, the index of serum vitamin D status, by CYP27B1, which is originally found in kidneys but recently detected in non-renal tissues. 25(OH)D has been shown to repress some cancers expressing CYP27B1 due to the local conversion of 25(OH)D to 1α,25(OH)2D, which works in a intra-, auto-, or paracrine manner and thus minimizes the risk of hypercalcemia. In this study, we found CYP27B1 expression in human hepatocyte, HCC, and HepG2 cells. As we treated HepG2 cells with 25(OH)D, the 1α,25(OH)2D target gene CYP24A1 expression was increased and was further upregulated as CYP27B1 transfection or downregulated as CYP27B1 knockdown. Other 1α,25(OH)2D target genes in HepG2 cells, p21 and p27 were also stimulated by 25(OH)D after CYP27B1 transfection. Further, 25(OH)D could inhibit HepG2 cells growth, which was potentiated by CYP27B1 transfection. Collectively, we showed for the first time that HCC expressed CYP27B1 and was able to covert 25(OH)D to 1α,25(OH)2D in vitro, thus responsive to 25(OH)D treatment. Our data justifies the application of 25(OH)D and CYP27B1 gene transfection therapy in further HCC treatment studies.
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Keelung 204, Taiwan, ROC.
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Chiang
authors.affiliation: Gastroenterology Department, Chang Gung Memorial Hospital, Chang Gung University, Keelung 204, Taiwan, ROC.
authors.forename: Cho-Li
authors.initials: CL
authors.lastname: Yen
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan, ROC.
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Yeh
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan, ROC.
authors.forename: Jun-Te
authors.initials: JT
authors.lastname: Hsu
authors.affiliation: Gastroenterology Department, Chang Gung Memorial Hospital, Chang Gung University, Keelung 204, Taiwan, ROC.
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Chen
authors.affiliation: Department of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, ROC.
authors.forename: Sheng-Fong
authors.initials: SF
authors.lastname: Kuo
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan, ROC.
authors.forename: Shang-Yu
authors.initials: SY
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, ROC.
authors.forename: Chi-Chin
authors.initials: CC
authors.lastname: Sun
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
authors.affiliation: Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Tai C
authors.initials: TC
authors.lastname: Chen
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan, ROC.
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.affiliation: Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, TaoYuan, Taiwan, ROC.
authors.forename: Shu-Yuan
authors.initials: SY
authors.lastname: Hsu
authors.affiliation: Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, TaoYuan, Taiwan, ROC. Electronic address: hhj143@mail.cgu.edu.tw.
authors.forename: Horng-Heng
authors.initials: HH
authors.lastname: Juang
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; C104450:25-hydroxyvitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase
keywords: 25-Hydroxyvitamin D; CYP24A1; CYP27B1; Gene therapy; HCC; HepG2