Abstract
The aryl hydrocarbon receptor nuclear translocator (ARNT) is broadly involved in regulating tumorigenesis by inducing genes that are involved in tumor growth and angiogenesis. Tumorigenesis usually involves normoxic conditions. However, the role of ARNT in tumor metastasis during normoxia remains unclear. Here, we demonstrate that ARNT protein levels were decreased in late-stage human colorectal cancer using immunohistochemical analysis. Down-regulation of ARNT protein promoted cancer cell migration and invasion, which was mediated by activation of the fibronectin/integrin β1/FAK signaling axis. In addition, the enhancement of migration and invasion in ANRT knockdown cells was blocked when ARNT was restored in the cells. In xenografts in severe combined immunodeficiency mice, tumor growth was significantly inhibited in the ARNT-knockdown condition. However, the tail-vein injection animal model revealed that the depletion of ARNT-induced metastatic lung colonies was further enhanced when ARNT expression was recovered post-injection. Interestingly, chemotherapeutic drugs inhibited ARNT expression and promoted the invasion of residual tumor cells. These results suggest that ARNT may play a positive role during tumor growth (either in early-stage tumor growth or in organ metastases), but plays a negative role in tumor migration and invasion. Therefore, the efficiency of ARNT-targeted therapy during different cancer stages should be carefully evaluated.
Highlights
The aryl hydrocarbon receptor (AHR) nuclear translocator (ARNT) ( known as hypoxia-inducible factor (HIF)-1β) is a member of the basic helix-loophelix PER/AHR/aryl hydrocarbon receptor nuclear translocator (ARNT)/SIM family of transcription factors [1]
ARNT is constitutively expressed in a wide range of tissues, and its expression is correlated with tumorigenesis [8]
The hypoxia-induced promoter contains hypoxia response element (HRE) binding sites (Supplementary Figure S1), and its activity was inhibited in shARNT cells, indicating the loss of ARNT function in shARNT cells
Summary
The aryl hydrocarbon receptor (AHR) nuclear translocator (ARNT) ( known as hypoxia-inducible factor (HIF)-1β) is a member of the basic helix-loophelix PER/AHR/ARNT/SIM (bHLH-PAS) family of transcription factors [1]. ARNT forms a heterodimer with HIF-1α in response to varying oxygen levels within microenvironments and promotes cell survival and angiogenesis [6, 7]. Loss of HIF-1α and ARNT leads to an increased response to radiotherapy, a reduction in tumor growth, and decreased angiogenesis in tumors transplanted into immune-deficient mice [8]. These studies indicate that ARNT interacts with specific transcription factors in response to environmental conditions to trigger the signaling of tumorigenesis under either normoxic or hypoxic conditions. ARNT expression has been documented in several cancers. The expression of ARNT in tumors appears to be a prognostic biomarker and a target for cancer therapies
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