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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

Evaluation of ARNT2 expression in primary OSCCs. (A) The ARNT2 IHC scores in adjacent normal oral tissues and OSCCs range from 40 to 180 (median, 135) and 10 to 157 (median, 75), respectively. The IHC scores in primary OSCCs are significantly (*P < 0.05) lower than in normal oral tissues. Representative IHC results for ARNT2 protein in (B) normal oral tissue and primary (C) OSCC. Strong ARNT2 immunoreactivity is seen in normal oral tissues, whereas the OSCCs show almost negative immunostaining. Original magnification, x 100. (D) ROC curve analysis shows the optimal cutoff value is 107.5 (area under the curve, 0.896; 95% CI, 0.8201-0.9438; *P < 0.05). (E) The Youden index (sensitivity, 85.0%; specificity, 83.3%; *P < 0.05) also shows that the optimal cutoff value is 107.5. AUC, area under the curve.
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Figure 2: Evaluation of ARNT2 expression in primary OSCCs. (A) The ARNT2 IHC scores in adjacent normal oral tissues and OSCCs range from 40 to 180 (median, 135) and 10 to 157 (median, 75), respectively. The IHC scores in primary OSCCs are significantly (*P < 0.05) lower than in normal oral tissues. Representative IHC results for ARNT2 protein in (B) normal oral tissue and primary (C) OSCC. Strong ARNT2 immunoreactivity is seen in normal oral tissues, whereas the OSCCs show almost negative immunostaining. Original magnification, x 100. (D) ROC curve analysis shows the optimal cutoff value is 107.5 (area under the curve, 0.896; 95% CI, 0.8201-0.9438; *P < 0.05). (E) The Youden index (sensitivity, 85.0%; specificity, 83.3%; *P < 0.05) also shows that the optimal cutoff value is 107.5. AUC, area under the curve.

Mentions: We analyzed the ARNT2 protein expression in primary OSCCs from 100 patients using the IHC scoring system 33-39. The ARNT2 IHC scores in adjacent normal oral tissues and OSCCs ranged from 40 to 180 (median, 135) and 10 to 157 (median, 75). The IHC scores in the primary OSCCs were significantly (P < 0.05) lower than in normal oral tissues (Fig. 2A). Fig. 2B and C, respectively, show representative IHC results for ARNT2 protein in adjacent normal oral tissue and primary OSCCs. Strong ARNT2 immunoreactivity was detected in the nuclei of normal tissues, whereas the OSCC tissues showed almost negative immunostaining. To determine an optimal cutoff point of the identified IHC scores, we used ROC curve analysis and the Youden index. The ROC curve analysis (area under the curve, 0.896; 95% confidence interval [CI], 0.8201-0.9438; P < 0.05) and Youden index (sensitivity, 85.0%; specificity, 83.3%; P < 0.05) showed that the cutoff value was 107 (Fig. 2D, E). Table 1 shows the correlations between the clinicopathological characteristics of the patients with OSCC and the status of ARNT2 protein expression. Among the clinical parameters, the ARNT2 expression level was significantly (P < 0.05) related to the primary tumoral size of the OSCCs.


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)

Evaluation of ARNT2 expression in primary OSCCs. (A) The ARNT2 IHC scores in adjacent normal oral tissues and OSCCs range from 40 to 180 (median, 135) and 10 to 157 (median, 75), respectively. The IHC scores in primary OSCCs are significantly (*P < 0.05) lower than in normal oral tissues. Representative IHC results for ARNT2 protein in (B) normal oral tissue and primary (C) OSCC. Strong ARNT2 immunoreactivity is seen in normal oral tissues, whereas the OSCCs show almost negative immunostaining. Original magnification, x 100. (D) ROC curve analysis shows the optimal cutoff value is 107.5 (area under the curve, 0.896; 95% CI, 0.8201-0.9438; *P < 0.05). (E) The Youden index (sensitivity, 85.0%; specificity, 83.3%; *P < 0.05) also shows that the optimal cutoff value is 107.5. AUC, area under the curve.
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Figure 2: Evaluation of ARNT2 expression in primary OSCCs. (A) The ARNT2 IHC scores in adjacent normal oral tissues and OSCCs range from 40 to 180 (median, 135) and 10 to 157 (median, 75), respectively. The IHC scores in primary OSCCs are significantly (*P < 0.05) lower than in normal oral tissues. Representative IHC results for ARNT2 protein in (B) normal oral tissue and primary (C) OSCC. Strong ARNT2 immunoreactivity is seen in normal oral tissues, whereas the OSCCs show almost negative immunostaining. Original magnification, x 100. (D) ROC curve analysis shows the optimal cutoff value is 107.5 (area under the curve, 0.896; 95% CI, 0.8201-0.9438; *P < 0.05). (E) The Youden index (sensitivity, 85.0%; specificity, 83.3%; *P < 0.05) also shows that the optimal cutoff value is 107.5. AUC, area under the curve.
Mentions: We analyzed the ARNT2 protein expression in primary OSCCs from 100 patients using the IHC scoring system 33-39. The ARNT2 IHC scores in adjacent normal oral tissues and OSCCs ranged from 40 to 180 (median, 135) and 10 to 157 (median, 75). The IHC scores in the primary OSCCs were significantly (P < 0.05) lower than in normal oral tissues (Fig. 2A). Fig. 2B and C, respectively, show representative IHC results for ARNT2 protein in adjacent normal oral tissue and primary OSCCs. Strong ARNT2 immunoreactivity was detected in the nuclei of normal tissues, whereas the OSCC tissues showed almost negative immunostaining. To determine an optimal cutoff point of the identified IHC scores, we used ROC curve analysis and the Youden index. The ROC curve analysis (area under the curve, 0.896; 95% confidence interval [CI], 0.8201-0.9438; P < 0.05) and Youden index (sensitivity, 85.0%; specificity, 83.3%; P < 0.05) showed that the cutoff value was 107 (Fig. 2D, E). Table 1 shows the correlations between the clinicopathological characteristics of the patients with OSCC and the status of ARNT2 protein expression. Among the clinical parameters, the ARNT2 expression level was significantly (P < 0.05) related to the primary tumoral size of the OSCCs.

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