Acylglycerol kinase promotes tumour growth and metastasis via activating the PI3K/AKT/GSK3β signalling pathway in renal cell carcinoma

Abstract

Background: Clinically, 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. Methods: AGK 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. Results: AGK 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. Conclusions: AGK 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.

WTAP promotes osteosarcoma tumorigenesis by repressing HMBOX1 expression in an m6A-dependent manner

“…S2B). PI3K/AKT signaling pathway promotes the growth, migration, and invasion of various cancers including osteosarcoma 47,48 . We hypothesized that WTAP/HMBOX1 was involved in the progression of osteosarcoma via regulating PI3K/AKT signaling pathway.…”

Acylglycerol kinase promotes the stemness of nasopharyngeal carcinoma cells by promoting β‐catenin translocation to the nucleus through activating PI3K/Akt pathway

“…Further KEGG enrichment analysis showed that the PI3K/Akt signaling pathway is mostly enriched in cells with ectopic expression of AGK. Notably, the previous studies have indicated that AGK can activate the PI3K/Akt pathway in breast cancer 19 and renal cell carcinom 17 . These results promoted us to focus on exploring whether PI3K/Akt pathway is responsible for AGK‐mediated effects on NPC cell stemness.…”

“…We used the inhibitor of PI3K/Akt in NPC cells with AGK overexpression and the activator of PI3K/Akt in NPC cells with AGK knockdown, and found that the PI3K/Akt pathway is necessary for AGK‐mediated effects on NPC cell stemness. However, since there are many downstream effectors of the PI3K/Akt pathway, we referred to the previous studies showing that Akt can phosphorylate GSK3β which sequentially increases β‐catenin accumulation in nucleus and thus β‐catenin activity 17 . Additionally, β‐catenin accumulation in nucleus has been confirmed to enhance the stemness in various cancers, 7,16,29 thus, we continued to investigate whether β‐catenin acts as the downstream effector of the PI3K/Akt pathway, and mediates the AGK‐inducing effects on NPC cell stemness.…”

The correlation and clinical significance of PIK3CA, PIK3CB and HPV infection in esophageal squamous cell carcinoma

“…Its abnormal activation promotes the normal development of cells to cancer cells. An abnormal PI3K/Akt signal transduction is present in many human malignant tumors [30][31][32][33]. As a catalytic subunit of PI3K, PI3Kp110 has four members, namely, P110α, P110β, P110δ, and P110γ.…”