Abstract
Patients with clear cell renal cell carcinoma (ccRCC) are often diagnosed with both von Hippel-Lindau (VHL) mutations and the constitutive activation of hypoxia-inducible factor-dependent signaling. In this study, we investigated the effects of long-term hypoxia in 786-O, a VHL-defective renal cell carcinoma cell line, to identify potential genes and microRNAs associated with tumor malignancy. The transcriptomic profiles of 786-O under normoxia, short-term hypoxia and long-term hypoxia were analyzed using next-generation sequencing. The results showed that long-term hypoxia promoted the ability of colony formation and transwell migration compared to normoxia. In addition, the differentially expressed genes induced by long-term hypoxia were involved in various biological processes including cell proliferation, the tumor necrosis factor signaling pathway, basal cell carcinoma and cancer pathways. The upregulated (L1CAM and FBN1) and downregulated (AUTS2, MAPT, AGT and USH1C) genes in 786-O under long-term hypoxia were also observed in clinical ccRCC samples along with malignant grade. The expressions of these genes were significantly correlated with survival outcomes in patients with renal cancer. We also found that long-term hypoxia in 786-O resulted in decreased expressions of hsa-mir-100 and hsa-mir-378 and this effect was also observed in samples of metastatic ccRCC compared to samples of non-metastatic ccRCC. These findings may provide a new direction for the study of potential molecular mechanisms associated with the progression of ccRCC.
Highlights
Renal cell carcinoma (RCC) includes various malignancies that originate in the epithelium of renal tubules [1]
To avoid exposing the hypoxia-incubated cells to a normoxic environment during the subculture procedure, we maintained the cells in a pysiological oxygen workstations InvivO2 400 system so that the subculture could be performed in hypoxic conditions
Sci. 2017, 18, 2657 the 786-O cells grown in long-term hypoxic conditions exhibited increased colony formation and transwell migration ability compared to normoxia (Figure 1B,C), indicating that long-term hypoxia promoted 786-O to become more aggressive
Summary
Renal cell carcinoma (RCC) includes various malignancies that originate in the epithelium of renal tubules [1]. It is the most common form of adult kidney cancer, accounting for approximately 90–95% of cases. Partial or complete removal of the affected kidneys has been reported to be the initial treatment for ccRCC in 75–80% of cases [2,3]. Surgery is the treatment of choice for localized RCC, metastasis develops in 20–30% of patients with limited disease at the time of surgery. The 5-year survival rate in patients with advanced RCC is low and the reported time to relapse after nephrectomy ranges from 15 to 18 months [6]. The risk factors for RCC have been reported to be associated with carcinogens, chronic kidney inflammation and genetic alterations [7], further studies are needed to elucidate the etiology
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