Suppression of AQP7 is Crucial for Proliferation and Lipid Metabolism in ccRCC

Abstract Background: It is well-established that reprogramming of lipid metabolism is a feature of clear cell renal cell carcinoma (ccRCC), which also acts as a driving force in oncogenesis induced by hypoxia-inducible factors (HIFs) in ccRCC. Aquaporin 7 (AQP7), a channel facilitates glycerol to pass through the membrane and induces a decrease in triglycerides (TGs) and glycerol in adipocytes. However, whether AQP7 takes a part in the lipid metabolism and malignant behaviors of ccRCC is still unclear. Methods: The prognosis and diagnostic value of AQP7 in ccRCC were first evaluated by bioinformatics methods including TCGA database, Cox regression, etc. The expression of AQP7 was tested with tissue microarray and IHC. After AQP7 was stably upregulated by lentivirus transfection, cell viability, colony formation, and flow cytometry were performed. According to GSEA, Nile red staining was then used to detect lipid droplet accumulation, and relevant mechanisms and pathways were verified through Western blotting and qPCR. Results: AQP7 was suppressed in both TCGA and the tissue microarray cohort, and the prognosis was worse for patients with lower AQP7 levels, including OS, DSS and PFI. Multiple lipid metabolism pathways, especially the PPARα pathway, were activated in the cohort with high AQP7 expression based on gene set enrichment analysis (GSEA). Moreover, AQP7 overexpression in ccRCC inhibited the proliferation ability, reduced the TG and glycerol contents, and led to cell cycle arrest. As a crucial transcription factor relevant to lipid metabolism, the ability of PPARα to bind to PPRE and the expression levels of PPARα, were both upregulated by AQP7 overexpression, as was the expression of a series of genes targeted by PPARα. Furthermore, downregulating HIF-1β and HIF-2α could elevate the expression levels of AQP7 and PPARα in ccRCC. Conclusions: AQP7 is suppressed in ccRCC and AQP7 may be a promising prognostic marker for the disease. Suppression of AQP7 in ccRCC contributes to lipid metabolism and cell cycle acceleration. The HIF/AQP7/PPARα axis might be an avenue for ccRCC treatment targeting lipid metabolism.