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Author Ishida, Sho ♦ Kasamatsu, Atsushi ♦ Endo-Sakamoto, Yosuke ♦ Nakashima, Dai ♦ Koide, Nao ♦ Takahara, Toshikazu ♦ Shimizu, Toshihiro ♦ Iyoda, Manabu ♦ Shiiba, Masashi ♦ Tanzawa, Hideki ♦ Uzawa, Katsuhiro
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ CELL CYCLE ♦ CELL PROLIFERATION ♦ CHELATING AGENTS ♦ PLANT GROWTH ♦ UPTAKE ♦ ZINC CHLORIDES
Abstract Zrt-Irt-like protein 4 (ZIP4) is critical molecule for proper mammalian development and releasing zinc from vesicular compartments. Recent studies suggested that ZIP4 plays an important role of tumor progression in pancreatic, prostate, and hepatocellular cancers, however, little is known about the detail mechanism of ZIP4 in their cancers. In the present study, we examined the possibility of ZIP4 as a new molecular target for oral squamous cell carcinoma (OSCC). We evaluated ZIP4 expression in OSCC-derived cell lines and primary OSCC samples by quantitative RT-PCR, immunoblotting, and immunohistochemistry (IHC). We also analyzed the clinical correlation between ZIP4 status and clinical behaviors in patients with OSCC. In addition, ZIP4 knockdown cells (shZIP4 cells) and ZnCl{sub 2} treatment were used for functional experiments, including cellular proliferation assay, zinc uptake assay, and cell-cycle analysis. ZIP4 mRNA and protein were up-regulated significantly in OSCCs compared with normal counterparts in vitro and in vivo. IHC showed that ZIP4 expression in the primary OSCC was positively correlated with primary tumoral size. The shZIP4 cells showed decrease accumulation of intercellular zinc and decreased cellular growth by cell-cycle arrest at the G1 phase, resulting from up-regulation of cyclin-dependent kinase inhibitors and down-regulation of cyclins and cyclin-dependent kinases. Since cellular growth of OSCC cells after treatment with zinc was significantly greater than control cells, we speculated that intercellular ZnCl{sub 2} accumulation is an important factor for cellular growth. Consistent with our hypothesis, not only decreased zinc uptake by ZIP4 knockdown but also chelating agent, N,N,N′,N′-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN), showed inhibitory effects of cellular proliferation. Therefore, our data provide evidence for an essential role of ZIP4 and intracellular zinc for tumoral growth in OSCC, suggesting that zinc uptake might be a potential therapeutic targeting event for OSCCs. - Highlights: • ZIP4 contributes to tumor progression in OSCCs. • ZIP4 regulated the cell-cycle arrest at G1/S phase in OSCC cells. • Intercellular ZnCl{sub 2} accumulation is an important factor for cellular growth. • TPEN, a chelating agent, might be a new therapeutic tool for the patients with OSCC. • ZIP4 would be a potential therapeutic target for OSCCs.
ISSN 0006291X
Educational Use Research
Learning Resource Type Article
Publisher Date 2017-01-29
Publisher Place United States
Journal Biochemical and Biophysical Research Communications
Volume Number 483
Issue Number 1


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