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The circadian rhythms in mammals are
regulated by a pacemaker located in the suprachiasmatic nucleus of the
hypothalamus. The clock gene family, i.e., Clock,
Bmal, Per, Cry and Dec, are involved in a
transcription-translation feedback loop that generates the circadian rhythm at
the intracellular level. Clock gene products DEC1 and DEC2 are
basic-helix-loop-helix (bHLH) transcription factors, and are involved in
cellular differentiation, responses to hypoxia and circadian rhythms. We
recently showed that the expression of DEC1 and DEC2 was up-regulated by
hypoxia; however, the functions of these two factors under hypoxic conditions
have not been elucidated in detail. The present keynote talk demonstrates two
projects: (1) Vascular Endothelial Growth Factor (VEGF); and (2)
Epithelial-Mesenchymal Transition (EMT). (1) The expression of VEGF in response
to hypoxia depends on transcriptional activation by a heterodimer comprising
hypoxia-inducible factor 1a (HIF-1a) and Aryl Hydrocarbon Receptor Nuclear Translocator 1 (ARNT1). In
the present study, we showed that DEC2, but not DEC1, suppressed VEGF gene
expression under hypoxic conditions. DEC2 protein was co-immunoprecipitated
with HIF-1a but not with ARNT1. The binding of HIF-1a to the Hypoxia Response
Element (HRE) in the VEGF promoter was decreased by DEC2 overexpression and
increased by DEC2 knockdown. We also showed that the circadian expression of
VEGF showed a reciprocal pattern to that of DEC2 in cartilage. DEC2 had a
circadian oscillation in implanted Sarcoma 180 cells. We conclude that DEC2
negatively regulates VEGF expression and plays an important role in the
pathological conditions in which VEGF is involved. (2) Epithelial-Mesenchymal
Transition (EMT) is an important step leading to invasion and migration of
various tumor cells and TGF-β treatment has been shown to induce cancer cells
to undergo EMT. We examined the role of DEC1 in EMT of PANC-1 cells, a human
pancreatic cancer cell line. As a result, we found that DEC1 was upregulated by
TGF-β in PANC-1 cells and regulated the expression and the levels of nuclear,
cytoplasmic or membrane localization of EMT-related factors, including
phosphorylated Smad3 (pSmad3), snail, claudin-4 and N-cadherin. In the presence
of TGF-β, DEC1 knockdown by siRNA inhibited morphological changes during EMT
processes; while TGF-β induced PANC-1 cells to taken on a spindle-shaped
morphology. Furthermore, a combination treatment of DEC1 expression with TGF-β
was closely linked to the migration and invasion of PANC-1 cells. These
findings suggest that DEC1 plays an important role in the regulation of these
EMT-related factors in pancreatic cancer.
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