FBXL18 升高促进 RPS15A 泛素化和 SMAD3 激活，从而驱动 HCC。
Elevated FBXL18 promotes RPS15A ubiquitination and SMAD3 activation to drive HCC.
机构信息
Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, P.R. China.
Department of Hepatobiliary Surgery, The Third Affiliated hospital of Chongqing Medical University, Chongqing, P.R. China.
出版信息
Hepatol Commun. 2023 Jun 28;7(7). doi: 10.1097/HC9.0000000000000198. eCollection 2023 Jul 1.
BACKGROUND
F-box and leucine-rich repeat protein 18 (FBXL18) is an E3 ubiquitin ligase that is reported to be involved in the tumorigenesis of various types of cancer. However, it remains unknown whether FBXL18 is correlated with hepatocarcinogenesis.
METHODS AND RESULTS
In the current study, we found that FBXL18 was highly expressed in HCC tissues and positively associated with poor overall survival of HCC patients. FBXL18 was an independent risk factor for HCC patients. We observed that FBXL18 drove HCC in FBXL18 transgenic mice. Mechanistically, FBXL18 promoted the K63-linked ubiquitination of small-subunit ribosomal protein S15A (RPS15A) and enhanced its stability, increasing SMAD family member 3 (SMAD3) levels and translocation to the nucleus and promoting HCC cell proliferation. Moreover, the knockdown of RPS15A or SMAD3 significantly suppressed FBXL18-mediated HCC proliferation. In clinical samples, elevated FBXL18 expression was positively associated with RPS15A expression.
CONCLUSION
FBXL18 promotes RPS15A ubiquitination and upregulates SMAD3 expression, leading to hepatocellular carcinogenesis, and this study provides a novel therapeutic strategy for HCC treatment by targeting the FBXL18/RPS15A/SMAD3 pathway.
背景
F-box 和亮氨酸丰富重复蛋白 18（FBXL18）是一种 E3 泛素连接酶，据报道它参与了多种类型癌症的肿瘤发生。然而，目前尚不清楚 FBXL18 是否与肝癌的发生有关。
方法和结果
在本研究中，我们发现 FBXL18 在 HCC 组织中高表达，并与 HCC 患者总体生存不良呈正相关。FBXL18 是 HCC 患者的独立危险因素。我们观察到 FBXL18 驱动 FBXL18 转基因小鼠发生 HCC。机制上，FBXL18 促进小亚基核糖体蛋白 S15A（RPS15A）的 K63 连接泛素化，增强其稳定性，增加 SMAD 家族成员 3（SMAD3）的水平和核转位，并促进 HCC 细胞增殖。此外，RPS15A 或 SMAD3 的敲低显著抑制了 FBXL18 介导的 HCC 增殖。在临床样本中，FBXL18 表达的升高与 RPS15A 的表达呈正相关。
结论
FBXL18 促进 RPS15A 的泛素化并上调 SMAD3 的表达，导致肝细胞癌的发生，本研究通过靶向 FBXL18/RPS15A/SMAD3 通路为 HCC 的治疗提供了一种新的治疗策略。
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