Elevated FBXO45 promotes TFG ubiquitination and drives lung metastasis of hepatocellular carcinoma

Abstract

Background & Aims

Elevated F-box/SPRY domain protein 1 (FBXO45) expression is associated with human hepatocellular carcinoma (HCC). While TP53 mutations represent a common genetic alteration in HCC, the potential regulatory interplay between TP53 and FBXO45 in modulating HCC progression remains unclear.

Methods

We analyzed the relationship between TP53 and FBXO45 in patients with HCC. A series of assays were also performed to explore the effect of FBXO45 on invasion and metastasis in TP53-mutated HCC cell lines and mouse models. These experimental findings were further validated in clinical samples.

Results

FBXO45 expression was upregulated in 78.3% (83/106) of patients with HCC with TP53 mutation, marking an aggressive subtype. Overexpression of FBXO45 significantly enhanced HCC cell migration and invasion capacity (p <0.001), whereas FBXO45 silencing suppressed these effects (p <0.01). Mechanistically, FBXO45 promoted Trk-fused gene (TFG) Lys103 ubiquitination and then increased its stability. This post-translational modification facilitates the binding of transcription factor activating transcription factor 2 (ATF2), leading to subsequent upregulation of nuclear factor-kappa B (NF-κB) p65 expression and ultimately promoting the migratory and invasive properties of TP53-mutant HCC cells. In vivo validation using an orthotopic xenograft model showed that FBXO45 overexpression significantly promoted HCC lung metastasis incidence (7/9 mice with metastases), whereas TFG knockdown abrogated this metastatic potential. Clinically, patients exhibiting high co-expression of FBXO45 and TFG defined an aggressive HCC subtype with significantly worse prognosis (p = 0.0015).

Conclusions

Our results provide new mechanistic insight into the role of FBXO45 in driving HCC invasion and metastasis. Therefore, targeting the TP53–FBXO45–TFG–ATF2–NF-κB axis represents a promising therapeutic approach for treating aggressive HCC with TP53 mutations.

Impact and implications

This study highlights that FBXO45 is highly expressed in patients with HCC with TP53 mutations. FBXO45 promotes HCC lung metastasis by activating the TFG–ATF2–NF-κB–epithelial–mesenchymal transition signaling axis. In addition, we found that targeting the TP53–FBXO45–TFG–ATF2–NF-κB axis could be a novel approach for the treatment of metastatic HCC.