Dysregulation of tumor-relevant proteins may contribute to human hepatocellular carcinoma (HCC) tumorigenesis. FBXO45 is an E3 ubiquitin ligase that is frequently elevated expression in human HCC. However, it remains unknown whether FBXO45 is associated with hepatocarcinogenesis and how to treat HCC patients with high FBXO45 expression. Here, IHC and qPCR analysis revealed that FBXO45 protein and mRNA were highly expressed in 54.3% (57 of 105) and 52.2% (132 of 253) of the HCC tissue samples, respectively. Highly expressed FBXO45 promoted liver tumorigenesis in transgenic mice. Mechanistically, FBXO45 promoted IGF2BP1 ubiquitination at the Lys190 and Lys450 sites and subsequent activation, leading to the upregulation of PLK1 expression and the induction of cell proliferation and liver tumorigenesis in vitro and in vivo. PLK1 inhibition or IGF2BP1 knockdown significantly blocked FBXO45-driven liver tumorigenesis in FBXO45 transgenic mice, primary cells and HCCs. Furthermore, IHC analysis on HCC tissue samples revealed a positive association between the hyperexpression of FBXO45 and PLK1/IGF2BP1, and both had positive relationship with poor survival in HCC patients. Thus, FBXO45 plays an important role in promoting liver tumorigenesis through IGF2BP1 ubiquitination and activation, and subsequent PLK1 upregulation, suggesting a new strategy for treating HCC by targeting FBXO45/IGF2BP1/PLK1 axis.
All data analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures and Figure supplements contain images of gels or blots. Source data files have been provided for the original files of the gels or blots,named as"Source data 1（blot images）". Source data files have been provided for the clinical and pathological data for HCC patients, namedas"Figure 1-source data 1". Source data files have been provided for interacted proteins or ubiquitinated proteins, namedas"Supplementary file 4. FBXO45-interacting proteins identified by Co IP-MS".
The Cancer Genome Atlas Pan-Cancer Analysis ProjectGDC Data Portal, doi:10.1038/ng.2764.
Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinomaNCBI Gene Expression Omnibus, GSE6764.
Gene expression patterns in human liver cancersNCBI Gene Expression Omnibus, GSE3500.
- Chuan-Ming Xie
- Chuan-Ming Xie
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of Army Medical University and complied with all relevant ethical regulations.(AMUWEC2020936).
Human subjects: All human subjects were approved by the Ethics Committee of Southwest Hospital, and all of the patients provided informed consent. Certificate NO. KY2020127.
- Haim Werner, Sackler School of Medicine, Tel Aviv University, Israel
© 2021, Lin et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.