Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA.
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
Mol Metab. 2020 Apr;34:136-145. doi: 10.1016/j.molmet.2020.01.011. Epub 2020 Feb 3.
The most common kidney cancer, clear cell renal cell carcinoma (ccRCC), is closely associated with obesity. The "clear cell" variant of RCC gets its name from the large lipid droplets that accumulate in the tumor cells. Although renal lipid metabolism is altered in ccRCC, the mechanisms and lipids driving this are not well understood.
We used shotgun lipidomics in human ccRCC tumors and matched normal adjacent renal tissue. To assess MBOAT7s gene expression across tumor severity, we examined histologically graded human ccRCC samples. We then utilized genome editing in ccRCC cell lines to understand the role of MBOAT7 in ccRCC progression.
We identified a lipid signature for ccRCC that includes an increase in arachidonic acid-enriched phosphatidylinositols (AA-PI). In parallel, we found that ccRCC tumors have increased expression of acyltransferase enzyme membrane bound O-acyltransferase domain containing 7 (MBOAT7) that contributes to AA-PI synthesis. In ccRCC patients, MBOAT7 expression increases with tumor grade, and increased MBOAT7 expression correlates with poor survival. Genetic deletion of MBOAT7 in ccRCC cells decreases proliferation and induces cell cycle arrest, and MBOAT7 cells fail to form tumors in vivo. RNAseq of MBOAT7 cells identified alterations in cell migration and extracellular matrix organization that were functionally validated in migration assays.
This study highlights the accumulation of AA-PI in ccRCC and demonstrates a novel way to decrease the AA-PI pool in ccRCC by limiting MBOAT7. Our data reveal that metastatic ccRCC is associated with altered AA-PI metabolism and identify MBOAT7 as a novel target in advanced ccRCC.
最常见的肾癌，透明细胞肾细胞癌（ccRCC），与肥胖密切相关。RCC 的“透明细胞”变体因其在肿瘤细胞中积累的大量脂滴而得名。尽管 ccRCC 中的肾脂代谢发生改变，但尚不清楚驱动这种改变的机制和脂质。
我们使用人类 ccRCC 肿瘤和匹配的正常相邻肾组织进行了 shotgun 脂质组学研究。为了评估 MBOAT7s 基因在肿瘤严重程度上的表达，我们检查了组织学分级的人类 ccRCC 样本。然后，我们利用 ccRCC 细胞系中的基因组编辑来了解 MBOAT7 在 ccRCC 进展中的作用。
我们确定了 ccRCC 的脂质特征，包括富含花生四烯酸的磷脂酰肌醇（AA-PI）的增加。同时，我们发现 ccRCC 肿瘤中酰基转移酶膜结合 O-酰基转移酶结构域包含 7（MBOAT7）的表达增加，有助于 AA-PI 的合成。在 ccRCC 患者中，MBOAT7 的表达随肿瘤分级增加，并且 MBOAT7 的高表达与不良预后相关。ccRCC 细胞中 MBOAT7 的基因缺失会降低增殖并诱导细胞周期停滞，并且 MBOAT7 细胞在体内无法形成肿瘤。MBOAT7 细胞的 RNAseq 鉴定出细胞迁移和细胞外基质组织改变，这些改变在迁移实验中得到了功能验证。
本研究强调了 AA-PI 在 ccRCC 中的积累，并证明了通过限制 MBOAT7 来减少 ccRCC 中 AA-PI 池的新方法。我们的数据表明转移性 ccRCC 与 AA-PI 代谢改变有关，并确定 MBOAT7 是晚期 ccRCC 的一个新靶标。
