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.

Hypoxic Upregulation of ARNT (HIF-1β): A Cell-Specific Attribute with Clinical Implications

“…In contrast to ARNT, ARNT2 is mainly expressed in the central nervous system [8,9]. ARNT2 expression was shown to be positively correlated with breast cancer prognosis [8]. In addition, high-ARNT2 levels in hepatocellular carcinomas are associated with a prolonged overall survival of cancer patients [8].…”

“…In contrast to ARNT, ARNT2 is mainly expressed in the central nervous system [8,9]. ARNT2 expression was shown to be positively correlated with breast cancer prognosis [8].…”

“…In addition, high-ARNT2 levels in hepatocellular carcinomas are associated with a prolonged overall survival of cancer patients [8]. However, many functions of this transcription factor are still unknown [1,8]. Moreover, the regulation of ARNT and ARNT2 varied in human hepatocellular carcinoma Hep3B cells.…”

“…ARNT2 expression was shown to be positively correlated with breast cancer prognosis [8]. In addition, high-ARNT2 levels in hepatocellular carcinomas are associated with a prolonged overall survival of cancer patients [8]. However, many functions of this transcription factor are still unknown [1,8].…”

“…ARNT and its paralogue ARNT2 [1] share a 90% identical amino acid sequence [8]. In contrast to ARNT, ARNT2 is mainly expressed in the central nervous system [8,9].…”