Abstract
BackgroundClinically, the median survival in patients with metastatic renal cell carcinoma (RCC) was only 6–12 months and a 5-year survival rate of less than 20%. Therefore, an in-depth study of the molecular mechanisms involved in RCC is of great significance for improving the survival of patients with advanced RCC. Acylglycerol kinase (AGK) is a newly discovered lipid kinase that has been reported to be a potent oncogene that may be involved in the regulation of malignant progression in a variety of tumours. However, the expression and biological characteristics of the AGK gene in RCC remain unclear.MethodsAGK expression was quantified by quantitative real-time PCR, Western blotting and immunohistochemistry in RCC cell lines and paired patient tissues. Kaplan-Meier method and Cox proportional hazards models were used to evaluate the prognostic value of AGK in human RCC tissue samples. Chi-squared test was performed to analyse the correlation between AGK expression and the clinicopathological features. Stable overexpression and knockdown of AGK in RCC cells was constructed with lentivirus. The oncogenic effects of AGK in human RCC progression were investigated using assays of colony formation, anchorage-independent growth, EdU assay, cell cycle analysis, wound-healing, trans-well analysis and xenograft tumour model. GSEA and KEGG analysis were conducted to detect the potential pathway of AGK involved in RCC. These results were further confirmed using the luciferase reporter assays, immunofluorescence and in vivo experiments.ResultsAGK expression is significantly elevated in RCC and closely related to the malignant development and poor prognosis in RCC patients. By in vitro and in vivo experiments, AGK was shown to enhance the proliferation of RCC cells by promoting the transition from the G1 phase to the S phase in the cell cycle and to enhance the migration and invasion by promoting epithelial-mesenchymal transition. By activating the PI3K/AKT/GSK3β signalling pathway in RCC, AGK can increase nuclear accumulation of β-catenin, which further upregulated TCF/LEF transcription factor activity.ConclusionsAGK promotes the progression of RCC via activating the PI3K/AKT/GSK3β signalling pathway and might be a potential target for the further research of RCC.
Highlights
Renal cell carcinoma (RCC) is the most common malignant cancer in the kidney [1]
Acylglycerol kinase (AGK) was shown to be elevated in seven renal cell carcinoma (RCC) cell lines (Caki-1, Caki-2, 786-O, A498, SK-RC-39, 769P and ACHN) compared to its level in immortalised renal epithelial cell lines HK-2 (Fig. 1d, e)
IHC staining of paraffin-embedded archived biopsies further demonstrated that AGK was hardly observed in the adjacent normal tissues, while strong AGK expression was detected in the tumour tissues (Fig. 1f)
Summary
Renal cell carcinoma (RCC) is the most common malignant cancer in the kidney [1]. Surgery may be curative for early-stage RCC patients, deaths from RCC have not declined mainly because of recurrence and metastatic disease [5]. Because of the lack of an effective treatment, the median survival time of patients with RCC is only 6–12 months, and the 5-year survival rate is less than 20% [6]. Recent studies have shown that more than 90% of kidney cancer-related deaths are associated with the metastasis of RCC [7]. The median survival in patients with metastatic renal cell carcinoma (RCC) was only 6– 12 months and a 5-year survival rate of less than 20%. The expression and biological characteristics of the AGK gene in RCC remain unclear
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