Zhou Huijun, Zeng Chong, Liu Jie, Luo Haijun, Huang Wei
Department of Gastroenterology and Urology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410083, China.
Department of Medicine, The Seventh Affiliated Hospital, Hengyang Medical School, University of South China, Changsha 410004, China.
Cancers (Basel). 2023 Feb 2;15(3):957. doi: 10.3390/cancers15030957.
The roles of F-box protein 43 (FBXO43) in carcinogenesis have been rarely revealed. The present study investigates the expression, function, and underlying mechanism of FBXO43 in hepatocellular carcinoma (HCC). Firstly, the expression and clinical significance of FBXO43 in HCC were investigated bioinformatically and experimentally using online omics data and local tissue samples. The role of N6-methyladenosine modification (m6A) of mRNA in regulating FBXO43 expression and the effects of m6A/FBXO43 axis alteration on cell proliferation and invasion were investigated further. Moreover, the underlying mechanism of the oncogenic FBXO43 was also explored. The results demonstrated that FBXO43 was significantly upregulated in HCC and was positively correlated with advanced progression and poor prognosis in patients. METTL3 and IGF2BP2 expressions were positively correlated with FBXO43 expression and served as the writer and reader of FBXO43 m6A, respectively, which stabilized and upregulated FBXO43 mRNA in HCC. FBXO43 silencing significantly reduced cell proliferation and invasion, and ectopic expression of FBXO43 could significantly restore the inhibitory effects caused by METTL3 and IGF2BP2 depletion in HCC cells. Mechanistically, FBXO43 depletion reduced the expression of UBE2C, a p53 ubiquitin-conjugating enzyme, suppressed proteasomal degradation of p53, and thus inhibited cell proliferation and invasion in HCC. In summary, the present study revealed that METTL3/IGF2BP2 mediated m6A contributed to the upregulation of FBXO43 that promoted the malignant progression of HCC by stimulating p53 degradation in a UBE2C-dependent manner, highlighting the promising application of FBXO43 as a target in HCC treatment.
F-box蛋白43（FBXO43）在肿瘤发生中的作用鲜有报道。本研究探讨FBXO43在肝细胞癌（HCC）中的表达、功能及潜在机制。首先，利用在线组学数据和局部组织样本，通过生物信息学和实验方法研究FBXO43在HCC中的表达及临床意义。进一步研究mRNA的N6-甲基腺苷修饰（m6A）在调节FBXO43表达中的作用，以及m6A/FBXO43轴改变对细胞增殖和侵袭的影响。此外，还探讨了致癌性FBXO43的潜在机制。结果表明，FBXO43在HCC中显著上调，且与患者的疾病进展和预后不良呈正相关。METTL3和IGF2BP2的表达与FBXO43的表达呈正相关，分别作为FBXO43 m6A的甲基转移酶和结合蛋白，使HCC中FBXO43 mRNA稳定并上调。FBXO43沉默显著降低细胞增殖和侵袭，而FBXO43的异位表达可显著恢复METTL3和IGF2BP2缺失对HCC细胞的抑制作用。机制上，FBXO43缺失降低了p53泛素结合酶UBE2C的表达，抑制了p53的蛋白酶体降解，从而抑制了HCC中的细胞增殖和侵袭。总之，本研究表明METTL3/IGF2BP2介导的m6A促进了FBXO43的上调，FBXO43通过以UBE2C依赖的方式刺激p53降解促进了HCC的恶性进展，突出了FBXO43作为HCC治疗靶点的应用前景。
