Abstract
In mammals, the circadian rhythm central generator consists of interactions among clock genes, including Per1/2/3, Cry1/2, Bmal1, and Clock. Circadian rhythm disruption may lead to increased risk of cancer in humans, and deregulation of clock genes has been implicated in many types of cancers. Among these genes, Per2 is reported to have tumor suppressor properties, but little is known about the correlation between Per2 and HIF, which is the main target of renal cell carcinoma (RCC) therapy. In this study, the rhythmic expression of the Per2 gene was not detectable in renal cancer cell lines, with the exception of Caki-2 cells. In Caki-2 cells, HIF1α increased the amplitude of Per2 oscillation by directly binding to the HIF-binding site located on the Per2 promoter. These results indicate that HIF1α may enhance the amplitude of the Per2 circadian rhythm.
Highlights
Renal cell carcinoma (RCC) is the most common malignancy of the adult kidney, which accounts for approximately 2% of cancers worldwide [1]
These results showed that the circadian rhythmicity of the Per2 gene was not detectable in renal cancer cell lines, excluding Caki-2 cells
Expression of clock genes in renal cancer cell lines To examine the difference between Caki-2 and other cell lines, we examined the expression of BMAL1, CLOCK, PER2, and CRY1 proteins
Summary
Renal cell carcinoma (RCC) is the most common malignancy of the adult kidney, which accounts for approximately 2% of cancers worldwide [1]. A somatic mutation of the Von Hippel–Lindau (VHL) gene is the most frequent genetic change observed in RCC [2], and recent efforts have targeted the VHL–hypoxia inducible factor (HIF)-mediated hypoxia-induced gene pathway for RCC therapy [3]. Hypoxia or mutations in the VHL gene inactivate this pathway. Vascular endothelial growth factor (VEGF) is one of the most potent pro-angiogenic factors, whose expression is transactivated by HIF1a/ARNT through binding to the hypoxia-response element (HRE) in the Vegf promoter [6,7]. Increased expression of VEGF is associated with malignant progression and a poor treatment outcome [8]. Suppressing the HIF-mediated gene pathway may be an important therapeutic strategy for the treatment of RCC [3]
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