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ARNT2 Regulates Tumoral Growth in Oral Squamous Cell Carcinoma.

Kimura Y, Kasamatsu A, Nakashima D, Yamatoji M, Minakawa Y, Koike K, Fushimi K, Higo M, Endo-Sakamoto Y, Shiiba M, Tanzawa H, Uzawa K - J Cancer (2016)

Bottom Line: 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.Our results proposed for the first time that the ARNT2 level is an indicator of cellular proliferation in OSCCs.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Oral Science, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;

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.

No MeSH data available.


Related in: MedlinePlus

Establishment of ARNT2 overexpressed cells. Significant (*P < 0.05, Mann-Whitney U test) up-regulation of (A) ARNT2 mRNA and (B) protein are observed in oeARNT2 cells compared with that in Mock cells using qRT-PCR and immunoblot analyses. Densitometric ARNT2 protein data are normalized to GAPDH protein levels. The values are expressed as a percentage of the Mock cells.
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Figure 3: Establishment of ARNT2 overexpressed cells. Significant (*P < 0.05, Mann-Whitney U test) up-regulation of (A) ARNT2 mRNA and (B) protein are observed in oeARNT2 cells compared with that in Mock cells using qRT-PCR and immunoblot analyses. Densitometric ARNT2 protein data are normalized to GAPDH protein levels. The values are expressed as a percentage of the Mock cells.

Mentions: Since frequent down-regulation of ARNT2 was observed in the OSCC-derived cells (Fig. 1), the OSCC-derived cells (HSC-3 and KOSC-2) were transfected with ARNT2 overexpression vector (oeARNT2) and control vector (Mock). To confirm the efficiency of the transfections, we performed qRT-PCR and immunoblot analyses (Fig. 3A, B). The ARNT2 mRNA expression level in the oeARNT2 cells was significantly (P < 0.05) greater than in the Mock cells (Fig. 3A). The ARNT2 protein level in the oeARNT2 cells also increased compared with the Mock cells (Fig. 3B).


ARNT2 Regulates Tumoral Growth in Oral Squamous Cell Carcinoma.

Kimura Y, Kasamatsu A, Nakashima D, Yamatoji M, Minakawa Y, Koike K, Fushimi K, Higo M, Endo-Sakamoto Y, Shiiba M, Tanzawa H, Uzawa K - J Cancer (2016)

Establishment of ARNT2 overexpressed cells. Significant (*P < 0.05, Mann-Whitney U test) up-regulation of (A) ARNT2 mRNA and (B) protein are observed in oeARNT2 cells compared with that in Mock cells using qRT-PCR and immunoblot analyses. Densitometric ARNT2 protein data are normalized to GAPDH protein levels. The values are expressed as a percentage of the Mock cells.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4829557&req=5

Figure 3: Establishment of ARNT2 overexpressed cells. Significant (*P < 0.05, Mann-Whitney U test) up-regulation of (A) ARNT2 mRNA and (B) protein are observed in oeARNT2 cells compared with that in Mock cells using qRT-PCR and immunoblot analyses. Densitometric ARNT2 protein data are normalized to GAPDH protein levels. The values are expressed as a percentage of the Mock cells.
Mentions: Since frequent down-regulation of ARNT2 was observed in the OSCC-derived cells (Fig. 1), the OSCC-derived cells (HSC-3 and KOSC-2) were transfected with ARNT2 overexpression vector (oeARNT2) and control vector (Mock). To confirm the efficiency of the transfections, we performed qRT-PCR and immunoblot analyses (Fig. 3A, B). The ARNT2 mRNA expression level in the oeARNT2 cells was significantly (P < 0.05) greater than in the Mock cells (Fig. 3A). The ARNT2 protein level in the oeARNT2 cells also increased compared with the Mock cells (Fig. 3B).

Bottom Line: 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.Our results proposed for the first time that the ARNT2 level is an indicator of cellular proliferation in OSCCs.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Oral Science, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;

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.

No MeSH data available.


Related in: MedlinePlus