HIF2α‐induced upregulation of RNASET2 promotes triglyceride synthesis and enhances cell migration in clear cell renal cell carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC), the most common malignant subtype of renal cell carcinoma, is characterized by the accumulation of lipid droplets in the cytoplasm. RNASET2 is a protein coding gene with a low expression level in ovarian cancers, but it is overexpressed in poorly differentiated neuroendocrine carcinomas. There is a correlation between RNASET2 upregulation and triglyceride expression levels in human serum but is unknown whether such an association is a factor contributing to lipid accumulation in ccRCC. Herein, we show that RNASET2 expression levels in ccRCC tissues and cell lines are significantly higher than those in both normal adjacent tissues and renal tubular epithelial cells. Furthermore, its upregulation is associated with increases in ccRCC malignancy and declines in patient survival. We also show that an association exists between increases in both cytoplasmic lipid accumulation and HIF‐2α transcription factor upregulation, and increases in both RNASET2 and triglyceride expression levels in ccRCC tissues. In addition, DGAT1 and DGAT2, two key enzymes involved in triglyceride synthesis, are highly expressed in ccRCC tissues. By contrast, RNASET2 knockdown inhibited their expression levels and lowered lipid droplet accumulation, as well as suppressing in vitro cell proliferation, cell invasion, and migration. In conclusion, our data suggest HIF2α upregulates RNASET2 transcription in ccRCC cells, which promotes both the synthesis of triglycerides and ccRCC migration. As such, RNASET2 may have the potential as a biomarker or target for the diagnosis and treatment of ccRCC.

Comprehensive analysis of LD-related genes signature for predicting prognosis and immunotherapy response in clear cell renal cell carcinoma

“…[31] The DGAT2 involved in lipid synthesis is modulated by RNASET2, consequently leading to an elevation in both triglyceride synthesis and the formation of lipid droplets within ccRCC cells. [35] Signi cant associations were found between the low expression of METTL7A and poor prognosis in KIRC. [36] SERPINF1 (PEDF) exhibits a negative correlation with anti-angiogenesis and a positive correlation with low tumor grade and pT stage.…”

Emergence of Lipid Droplets in the Mechanisms of Carcinogenesis and Therapeutic Responses

“…Glutathione peroxidase 8 (GPX8), knockout reduces LD levels (independent of lipid uptake), FA de novo synthesis, and triglyceride esterification in clear cell renal cell carcinoma (ccRCC), thus constituting a potential target in this cancer model [ 63 ]. In the same manner, RNASET2 knockout inhibits DGAT1 and 2 and reduces LD accumulation, concomitant with suppression of cell proliferation, migration, and invasion in ccRCC [ 64 ]. Thus, pharmacological inhibition of DGAT1 could be a potential target in ccRCC [ 64 , 65 ].…”

“…In the same manner, RNASET2 knockout inhibits DGAT1 and 2 and reduces LD accumulation, concomitant with suppression of cell proliferation, migration, and invasion in ccRCC [ 64 ]. Thus, pharmacological inhibition of DGAT1 could be a potential target in ccRCC [ 64 , 65 ]. In fact, various proteins could be targeted to disturb LD formation or accumulation for example, inhibition of the enzyme catalyzing esterification of FAs with coenzyme A, acyl-CoA synthetase 3 (ACSL3), disrupts LD accumulation in ccRCC and leads ferroptosis [ 66 ].…”

Lipid droplets: a candidate new research field for epithelial ovarian cancer

“…Extensive cellular lipid uptake and synthesis, followed by lipid droplet (LD) formation, can contribute to cancer progression ( Koizume and Miyagi, 2016 ; Cruz et al, 2020 ). Accumulated LDs play crucial roles in the expression of ccRCC phenotypes, such as cell motility ( Chen et al, 2022 ; Quan et al, 2023 ), invasiveness ( Chen et al, 2022 ), epithelial-to-mesenchymal transition ( Chen et al, 2022 ), and resistance to cell death ( Miess et al, 2018 ; Zhou et al, 2023 ). The LDs in ccRCC cells can also be catabolized by neutral lipases to release oleic acid on exposure to serum starvation and hypoxia (SSH), thereby maintaining cellular lipid homeostasis ( Ackerman et al, 2018 ).…”