Department of Histology, Embryology, Genetics and Developmental Biology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, China.
Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China.
FEBS Open Bio. 2023 Apr;13(4):638-654. doi: 10.1002/2211-5463.13570. Epub 2023 Feb 12.
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.
透明细胞肾细胞癌（ccRCC）是肾细胞癌中最常见的恶性亚型，其特征是细胞质中脂质滴的积累。RNASET2 是一种蛋白编码基因，在卵巢癌中的表达水平较低，但在低分化神经内分泌癌中过度表达。在人类血清中，RNASET2 的上调与甘油三酯表达水平之间存在相关性，但尚不清楚这种相关性是否是导致 ccRCC 脂质积累的因素之一。在此，我们表明，ccRCC 组织和细胞系中的 RNASET2 表达水平明显高于正常相邻组织和肾小管上皮细胞。此外，其上调与 ccRCC 恶性程度的增加和患者生存的下降有关。我们还表明，ccRCC 组织中细胞质脂质积累和 HIF-2α 转录因子上调的增加与 RNASET2 和甘油三酯表达水平的增加之间存在关联。此外，DGAT1 和 DGAT2，两种参与甘油三酯合成的关键酶，在 ccRCC 组织中高表达。相比之下，RNASET2 敲低抑制了它们的表达水平，降低了脂质滴的积累，并抑制了体外细胞增殖、细胞侵袭和迁移。总之，我们的数据表明，HIF2α 在 ccRCC 细胞中上调 RNASET2 的转录，促进了甘油三酯的合成和 ccRCC 的迁移。因此，RNASET2 可能具有作为 ccRCC 诊断和治疗的生物标志物或靶标的潜力。
