Abstract
p-Cresyl sulfate (pCS), a uremic toxin, can cause renal damage and dysfunction. Studies suggest that renal dysfunction increases the prevalence of renal cancer. However, the effect of pCS on the proliferation and migration of renal cancer is unclear. Clear cell renal cell carcinoma (ccRCC) expresses mutant von Hippel-Lindau gene and is difficult to treat. Hypoxia-inducible factor-1α and 2-α (HIF-1α and HIF-2α) as well as microRNA-21 (miR-21) can regulate the proliferation and migration of ccRCC cells. However, the association between HIF-α and miR-21 in ccRCC remains unclear. Therefore, the effects of pCS on ccRCC cells were investigated for HIF-α and miR-21 signals. Our results showed that pCS induced overexpression of HIF-1α and promoted the proliferation and regulated epithelial-mesenchymal transition-related proteins, including E-cadherin, fibronectin, twist and vimentin in ccRCC cells. pCS treatment increased miR-21 expression. Specifically, inhibition of miR-21 blocked pCS-induced proliferation and migration. Taken together, the present results demonstrate that pCS directly induced the proliferation and migration of ccRCC cells through mechanisms involving miR-21/HIF-1α signaling pathways.
Highlights
Indoxyl sulfate (IS) and p-cresyl sulfate are 2 types of uremic toxins metabolized from tryptophan and tyrosine, respectively, in the intestine and can cause renal dysfunction
We investigated whether p-cresyl sulfate (pCS)-induced proliferation was related to HIF-1α and HIF-2α. 786-O and A498 cells were treated with 100 or 200 μM pCS for 5 days
HIF-1α, HIF-2α, and VHL levels and the ratios of their expressions are shown in Fig. 2. pCS-induced cell proliferation of 786-O cells was related to HIF-1α signals and decreased levels of HIF-2α (Fig. 2a–d)
Summary
Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are 2 types of uremic toxins metabolized from tryptophan and tyrosine, respectively, in the intestine and can cause renal dysfunction. PCS can induce proliferation and migration of rat aortic vascular smooth muscle cells[20] and epithelial-mesenchymal transition (EMT) in kidney fibrosis[21]. Based on these studies, we predicted that pCS influences proliferation, EMT, and migration in ccRCC. Most patients with ccRCC have high expression of HIF-1α24, and studies have shown that HIF-1α plays an important role in the proliferation of ccRCC10,24,25 and regulates EMT in ccRCC and tubular epithelial cells[26,27]. The expression of HIF-α, EMT-related proteins, and migration were investigated in pCS-treated ccRCC cells in this study. The miR-21/HIF-1α axis signals were studied in pCS-treated ccRCC cells to examine cell proliferation and migration
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