Abstract
PurposeAccumulating literature has suggested that hZIP1 and HIF-1α play vital roles in the tumor process of clear cell renal cell carcinoma (ccRCC). However, the functional roles of hZIP1 and HIF-1α in ccRCC remain largely unknown.MethodsHIF-1α protein level was evaluated by a western blot in ccRCC tissues and cell lines. ccRCC cell lines were transfected with HIF-1α-siRNA to downregulate the expression level of HIF-1α. Then the proliferative, migratory and invasive abilities of ccRCC cells in vitro were detected by real-time cell analysis (RTCA) assay, wound healing assay and transwell assay, respectively. The role of HIF-1α in vivo was explored by tumor implantation in nude mice. Then the effect on glycolysis‐related proteins was performed by western blot after hZIP1 knockdown (overexpression) or HIF-1α knockdown. The effect on NF‐kB pathway was detected after hZIP1 overexpression.ResultsHIF-1α was markedly downregulated in ccRCC tissues compared with normal areas. But HIF-1α presented almost no expression in HK-2 and ACHN cells. Immunofluorescence indicated HIF-1α and PDK1 expression in both the cytoplasm and nucleus in ccRCC cells. Downregulation of HIF-1α suppressed ccRCC cell proliferation, migration, and invasion and resulted in smaller implanted tumors in nude mice. Furthermore, hZIP1 knockdown elevated HIF-1α protein levels and PDK1 protein levels in ccRCC cells. Interestingly, a sharp downregulated expression of HIF-1α was observed after hZIP1 overexpression in OSRC-2 and 786-O cells, which resulted from a downtrend of NF-kB1 moving into the cell nucleus.ConclusionOur work has vital implications that hZIP1 suppresses ccRCC progression by inhibiting NF-kB/HIF-1α pathway.
Highlights
Clear cell renal cell carcinoma is one of the most common malignant tumors in the urinary system, accounting for approximately 2–3% of malignant tumors in adults, and its incidence has been increasing steadily in our country
As shown by the Kaplan–Meier curve, there was no significant correlation between Hypoxia-inducible factor (HIF)-1a mRNA expression and overall survival status (Figure 1B)
Western blot assay was used to evaluate the expression of HIF1a in 32 cases of human Clear cell renal cell carcinoma (ccRCC)
Summary
Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors in the urinary system, accounting for approximately 2–3% of malignant tumors in adults, and its incidence has been increasing steadily in our country. The evolution of ccRCC is accompanied by changes in cell energy metabolism; that is, from aerobic phosphorylation to aerobic glycolysis (the Warburg effect) [4, 5]. Hypoxia-inducible factor (HIF) is a vital transcription factor and regulator of cell responses to hypoxic conditions and can be divided into HIF-1 and HIF-2. Hypoxia-inducible factor 1 (HIF-1) is a highly conserved member of the basic helix-loop-helix (bHLH) transcription factor family, which is composed of a and b subunit dimers. After the a and b subunits dimerize, relevant downstream genes such as glycolysis-related enzyme genes start to work, so HIF-1a and HIF-2a are probably key molecules for glycolysis and cell energy metabolism [6, 7]. In the study on the pathogenesis of ccRCC, the most prominent genes were all related to the expression of HIF-1a. Some downstream proteins such as VEGF are elevated to promote tumorigenesis progression [10]
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