Elevated FBXL6 expression in hepatocytes activates VRK2-transketolase-ROS-mTOR-mediated immune evasion and liver cancer metastasis in mice

Abstract

Metastatic hepatocellular carcinoma (HCC) is the most lethal malignancy and lacks effective treatment. FBXL6 is overexpressed in human hepatocellular carcinoma (HCC), but whether this change drives liver tumorigenesis and lung metastasis in vivo remains unknown. In this study, we aimed to identify FBXL6 (F-Box and Leucine Rich Repeat Protein 6) as a key driver of HCC metastasis and to provide a new paradigm for HCC therapy. We found that elevated FBXL6 expression in hepatocytes drove HCC lung metastasis and was a much stronger driver than Kras mutation (KrasG12D/+;Alb-Cre), p53 haploinsufficiency (p53+/-) or Tsc1 loss (Tsc1fl/fl;Alb-Cre). Mechanistically, VRK2 promoted Thr287 phosphorylation of TKT and then recruited FBXL6 to promote TKT ubiquitination and activation. Activated TKT further increased PD-L1 and VRK2 expression via the ROS-mTOR axis, leading to immune evasion and HCC metastasis. Targeting or knockdown of TKT significantly blocked FBXL6-driven immune evasion and HCC metastasis in vitro and in vivo. Notably, the level of active TKT (p-Thr287 TKT) was increased and was positively correlated with the FBXL6 and VRK2 expression levels in HCC patients. Our work provides novel mechanistic insights into FBXL6-driven HCC metastasis and suggests that targeting the TKT-ROS-mTOR-PD-L1/VRK2 axis is a new paradigm for treating patients with metastatic HCC with high FBXL6 expression.

Prognostic value and drug sensitivity of F‑box and leucine‑rich repeat protein 6 in glioma

“…3B ). Given the crucial role of FBXL6 in cancer ( 22 , 30 ), its expression levels were investigated across different stages of glioma. A tissue microarray comprising samples from 64 glioma patients was constructed for this purpose.…”

“…Low expression of FBXL6 was significantly associated with lower stromal and immune cores ( Fig. 8A ), which may contribute to tumor immune escape and suppression, thereby promoting glioblastoma progression ( 30 ). Similarly, in immune-infiltrating cells, low expression of FBXL6 was significantly correlated with CD4+ memory cells and monocytes, which was consistent with our previous results and may contribute to immune evasion and promote malignant progression in patients with glioblastoma ( 30 ).…”

“…8A ), which may contribute to tumor immune escape and suppression, thereby promoting glioblastoma progression ( 30 ). Similarly, in immune-infiltrating cells, low expression of FBXL6 was significantly correlated with CD4+ memory cells and monocytes, which was consistent with our previous results and may contribute to immune evasion and promote malignant progression in patients with glioblastoma ( 30 ). Additionally, a high expression level of FBXL6 was significantly associated with M0 macrophages ( Fig.…”

Identification of candidate genes associated with milk production and mastitis based on transcriptome‐wide association study

“…of mastitis cows. Furthermore, FBXL6 is overexpressed in human hepatocellular carcinoma and liver cancer (Zhang et al., 2023).…”

Robust machine−learning based prognostic index using cytotoxic T lymphocyte evasion genes highlights potential therapeutic targets in colorectal cancer

“…ZNF652 acts as a potential biomarker for immunotherapy in triple−negative breast cancer because its loss is related to PD−L1−mediated immune evasion [ 16 ]. FBXL6 overexpression in hepatocytes activates immune evasion in hepatocellular carcinoma [ 17 ]. In a recent investigation [ 18 ], an extensive genome−wide CRISPR screening was conducted on diverse genetically modified mouse cancer cell lines, cultured in conjunction with CTL; they identified 182 CTL evasion−related genes (CERGs), which can increase either the susceptibility or resilience of cancer cells to CTL−induced toxicity in mouse cancer models, were identified.…”