title: ARNT2 Regulates Tumoral Growth in Oral Squamous Cell Carcinoma.
abstract: Aryl hydrocarbon receptor nuclear translocator (ARNT) 2 is a transcriptional factor related to adaptive responses against cellular stress from a xenobiotic substance. Recent evidence indicates ARNT is involved in carcinogenesis and cancer progression; however, little is known about the relevance of ARNT2 in the behavior of oral squamous cell carcinoma (OSCC). In the current study, we evaluated the ARNT2 mRNA and protein expression levels in OSCC in vitro and in vivo and the clinical relationship between ARNT2 expression levels in primary OSCCs and their clinicopathologic status by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and immunohistochemistry. Using ARNT2 overexpression models, we performed functional analyses to investigate the critical roles of ARNT2 in OSCC. ARNT2 mRNA and protein were down-regulated significantly (P < 0.05 for both comparisons) in nine OSCC-derived cells and primary OSCC (n=100 patients) compared with normal counterparts. In addition to the data from exogenous experiments that ARNT2-overexpressed cells showed decreased cellular proliferation, ARNT2-positive OSCC cases were correlated significantly (P < 0.05) with tumoral size. Since von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase, a negative regulator of hypoxia-inducible factor (HIF1)-α, is a downstream molecule of ARNT2, we speculated that HIF1-α and its downstream molecules would have key functions in cellular growth. Consistent with our hypothesis, overexpressed ARNT2 cells showed down-regulation of HIF1-α, which causes hypofunctioning of glucose transporter 1, leading to decreased cellular growth. Our results proposed for the first time that the ARNT2 level is an indicator of cellular proliferation in OSCCs. Therefore, ARNT2 may be a potential therapeutic target against progression of OSCCs.
authors.affiliation: 1. Department of Oral Science, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: 2. Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasamatsu
authors.affiliation: 2. Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;
authors.forename: Dai
authors.initials: D
authors.lastname: Nakashima
authors.affiliation: 2. Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;
authors.forename: Masanobu
authors.initials: M
authors.lastname: Yamatoji
authors.affiliation: 1. Department of Oral Science, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Minakawa
authors.affiliation: 2. Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Koike
authors.affiliation: 2. Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Fushimi
authors.affiliation: 2. Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;
authors.forename: Morihiro
authors.initials: M
authors.lastname: Higo
authors.affiliation: 2. Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Endo-Sakamoto
authors.affiliation: 3. Department of Medical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Shiiba
authors.affiliation: 1. Department of Oral Science, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;; 2. Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;
authors.forename: Hideki
authors.initials: H
authors.lastname: Tanzawa
authors.affiliation: 1. Department of Oral Science, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;; 2. Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Uzawa
keywords: ARNT2; GLUT-1.; HIF1-α; VHL; cellular proliferation; oral squamous cell carcinoma