Li Wanyi, Gan Lingling, Zang Wenting, Chen Yan, Xu Bei
Department of Clinical Laboratory, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, People's Republic of China.
Department of Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, People's Republic of China.
Am J Physiol Cell Physiol. 2025 Jul 1;329(1):C283-C297. doi: 10.1152/ajpcell.00066.2025. Epub 2025 Jun 16.
Rac-GTPase-activating protein 1 (RACGAP1) is a member of the Rho GTPase-activating protein (GAP) family, which is involved in the process of cytokinesis. But its precise function in clear cell renal cell carcinoma (ccRCC) has not been extensively investigated. In this study, we found that RACGAP1 was regulated by centrosomal protein CEP55 and markedly facilitated the growth and progression of ccRCC in vitro and in vivo. In addition, RACGAP1 knockdown induces G1 phase arrest, resulting in mitotic disorder and subsequent apoptosis. These findings indicated that RACGAP1, a cell cycle-related gene, is crucial for the survival and growth of ccRCC. Furthermore, renal cancer is closely associated with metabolic processes. As demonstrated by our serum-targeted metabolomics study, RACGAP1 dysfunction altered the levels of multiple amino acids/amino acid derivatives, acylcarnitines, fatty acids/acyls, nucleotides, and their metabolites. Spatial metabolomics data further confirmed that downregulation of RACGAP1 expression could inhibit ccRCC growth not only by reprogramming fatty acid and nucleotide metabolism but also by interfering with lipid metabolism. More importantly, we detected higher levels of glutamine, acylcarnitines, and lipids in the tumor margin region, suggesting intratumor metabolic heterogeneity in ccRCC. In conclusion, this study elucidated the biological function of RACGAP1 in promoting ccRCC progression and revealed the regulatory mechanism of RACGAP1 in interfering with metabolic pathways from the perspective of multidimensional metabolomics. These findings will provide new targets and a theoretical basis for the treatment of RCC. We have demonstrated for the first time that CEP55 directly regulated RACGAP1 expression, and downregulation of RACGAP1 blocked ccRCC mitotic division at the G1 phase and induced apoptosis. Targeted and spatial metabolomics analyses showed that RACGAP1 disruption altered levels of multiple metabolites and inhibited ccRCC growth by reprogramming fatty acid, nucleotide, and lipid metabolism. Importantly, spatial imaging of metabolites uncovered intratumor metabolic heterogeneity in ccRCC, providing novel insights into the metabolic landscape of this malignancy.
Rac-GTP酶激活蛋白1（RACGAP1）是Rho GTP酶激活蛋白（GAP）家族的成员，参与胞质分裂过程。但其在透明细胞肾细胞癌（ccRCC）中的精确功能尚未得到广泛研究。在本研究中，我们发现RACGAP1受中心体蛋白CEP55调控，并在体外和体内显著促进ccRCC的生长和进展。此外，RACGAP1基因敲低诱导G1期阻滞，导致有丝分裂紊乱并随后发生凋亡。这些发现表明，RACGAP1作为一个细胞周期相关基因，对ccRCC的存活和生长至关重要。此外，肾癌与代谢过程密切相关。正如我们的血清靶向代谢组学研究所表明的，RACGAP1功能障碍改变了多种氨基酸/氨基酸衍生物、酰基肉碱、脂肪酸/酰基、核苷酸及其代谢物的水平。空间代谢组学数据进一步证实，RACGAP1表达下调不仅可通过重新编程脂肪酸和核苷酸代谢，还可通过干扰脂质代谢来抑制ccRCC生长。更重要的是，我们在肿瘤边缘区域检测到较高水平的谷氨酰胺、酰基肉碱和脂质，提示ccRCC存在肿瘤内代谢异质性。总之，本研究阐明了RACGAP在促进ccRCC进展中的生物学功能，并从多维代谢组学角度揭示了RACGAP1干扰代谢途径的调控机制。这些发现将为RCC的治疗提供新的靶点和理论基础。我们首次证明CEP55直接调控RACGAP1表达，RACGAP1下调在G1期阻断ccRCC有丝分裂并诱导凋亡。靶向和空间代谢组学分析表明，RACGAP1破坏改变了多种代谢物水平，并通过重新编程脂肪酸、核苷酸和脂质代谢抑制ccRCC生长。重要的是，代谢物的空间成像揭示了ccRCC的肿瘤内代谢异质性，为这种恶性肿瘤的代谢格局提供了新的见解。
