Lei Zhen, Luo Yiming, Lu Junli, Fu Qinggang, Wang Chao, Chen Qian, Zhang Zhiwei, Zhang Long
Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, People's Republic of China.
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang, People's Republic of China.
Cancer Gene Ther. 2025 Feb;32(2):198-213. doi: 10.1038/s41417-024-00861-w. Epub 2025 Jan 15.
The gene F-box only protein 22 (FBXO22) has been discovered to promote the development of liver cancer tumors. Nevertheless, there remains considerable ambiguity regarding the involvement of FBXO22 in the processes of angiogenesis and metastasis in hepatocellular carcinoma (HCC). Our study has confirmed a significant upregulation of FBXO22 expression in both HCC samples and cellular models. The increased level of FBXO22 correlates strongly with the number of tumors, presence of vascular invasion, and poor prognosis. Experimental investigations have shown that FBXO22 significantly enhances angiogenesis and metastasis of HCC both in vitro and in vivo. Mechanistically, FBXO22 interacts with and ubiquitinates 40S ribosomal protein S5 (RPS5) on Lys85, thereby promoting its K48-linked ubiquitin-mediated degradation in the cytoplasm. Following a decrease in the expression of RPS5, activation of downstream PI3K/AKT signaling pathway occurs, leading to elevated levels of HIF-1α and vascular endothelial growth factor A (VEGF-A). Our study has shown that FBXO22 facilitates HCC angiogenesis and metastasis via the RPS5/AKT/HIF-1α/VEGF-A signaling axis. Notably, inhibition of FBXO22 enhances the efficacy of Lenvatinib both in vitro and in vivo. Therefore, FBXO22 may present itself as a potential target for therapeutic intervention in the treatment of HCC.
已发现F盒蛋白22（FBXO22）基因可促进肝癌肿瘤的发展。然而，FBXO22在肝细胞癌（HCC）血管生成和转移过程中的作用仍存在相当大的不确定性。我们的研究证实，FBXO22在HCC样本和细胞模型中的表达均显著上调。FBXO22水平的升高与肿瘤数量、血管侵犯的存在以及不良预后密切相关。实验研究表明，FBXO22在体外和体内均能显著增强HCC的血管生成和转移。从机制上讲，FBXO22与40S核糖体蛋白S5（RPS5）在赖氨酸85处相互作用并使其泛素化，从而促进其在细胞质中由K48连接的泛素介导的降解。RPS5表达降低后，下游PI3K/AKT信号通路被激活，导致缺氧诱导因子-1α（HIF-1α）和血管内皮生长因子A（VEGF-A）水平升高。我们的研究表明，FBXO22通过RPS5/AKT/HIF-1α/VEGF-A信号轴促进HCC血管生成和转移。值得注意的是，抑制FBXO22在体外和体内均能增强乐伐替尼的疗效。因此，FBXO22可能是HCC治疗中潜在的治疗干预靶点。
