title: Liver X receptor reduces proliferation of human oral cancer cells by promoting cholesterol efflux via up-regulation of ABCA1 expression.
abstract: Liver X receptors (LXRs) contribute not only to maintain cholesterol homeostasis but also to control cell growth. However, the molecular mechanisms behind the LXR-mediated anti-proliferative effects are largely unknown. Here we show, by immunohistochemistry, that LXRα and LXRβ are differentially distributed in oral stratified squamous epithelia. By immunohistochemical and Western blot analyses, we also reveal that LXRα is abundantly expressed in human oral squamous cell carcinoma (HOSCC) tissues and cell lines. Cell counting, BrdU labeling and cell cycle assay indicated that LXR stimulation led to significant reduction of proliferation in HOSCC cells. Importantly, our study highlights, by using RNA interference, that the ATP-binding cassette transporter A1 (ABCA1)-accelerated cholesterol efflux is critical for the growth inhibitory action of LXRs in HOSCC cells. Moreover, we demonstrate that LXR activation reduces the growth of xenograft tumour of HOSCC cells in mice accompanied by the upregulation of ABCA1 expression and the decline of cholesterol levels in the tumour. These findings strongly suggested that targeting the LXR-regulated cholesterol transport, yielding in lowering intracellular cholesterol levels, could be a promising therapeutic option for certain types of cancers.
authors.affiliation: Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.|Division of Dentistry and Oral Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Tetsuharu
authors.initials: T
authors.lastname: Kaneko
authors.affiliation: Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.|Division of Dentistry and Oral Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Kanno
authors.affiliation: Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ichikawa-Tomikawa
authors.affiliation: Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Korehito
authors.initials: K
authors.lastname: Kashiwagi
authors.affiliation: Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Nanae
authors.initials: N
authors.lastname: Yaginuma
authors.affiliation: Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Ohkoshi
authors.affiliation: Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Mizuko
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugino
authors.affiliation: Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Imura
authors.affiliation: Division of Dentistry and Oral Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Chiba
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000818:Animals; D001692:Biological Transport / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D057093:Orphan Nuclear Receptors / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000235:genetics
chemical_list: D064286:ATP Binding Cassette Transporter 1; D002784:Cholesterol; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; C577833:Abca1 protein, mouse; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat
keywords: LXR; cell growth; metabolism; nuclear receptor; squamous cell carcinoma