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Targeting LEF1-mediated epithelial-mesenchymal transition reverses lenvatinib resistance in hepatocellular carcinoma
Xinxiu Li1, Hongmeng Su1, Wenqing Tang2
1Department of Medical Genetics and Developmental Biology, School of Medicine, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, Jiangsu, China.
Abstract:
Acquired resistance is a significant hindrance to clinical application of lenvatinib in unresectable hepatocellular carcinoma (HCC). Further in-depth investigation of resistance mechanisms can help to develop additional therapeutic strategies to overcome or delay resistance. In our study, two lenvatinib-resistant (LR) HCC cell lines were established by treatment with gradient increasing concentration of lenvatinib, named Hep3B-LR and HepG2-LR. Interestingly, continuous lenvatinib treatment reinforced epithelial-mesenchymal transition (EMT), cell migration, and cell invasion. Gene set enrichment analysis (GSEA) enrichment analysis of RNA-sequencing from Hep3B-LR and corresponding parental cells revealed that activation of Wnt signaling pathway was involved in this adaptive process. Active β-catenin and its downstream target lymphoid enhancer binding factor 1 (LEF1) were significantly elevated in LR HCC cells, which promoted lenvatinib resistance through mediating EMT-related genes. Data analysis based on Gene Expression Omnibus (GEO) and the Cancer Genome Atlas Program (TCGA) databases suggests that LEF1, as a key regulator of EMT, was a novel molecular target linked to lenvatinib resistance and poor prognosis in HCC. Using a small-molecule specific inhibitor ICG001 and knocking down LEF1 showed that targeting LEF1 restored the sensitivity of LR HCC cells to lenvatinib. Our results uncover upregulation of LEF1 confers lenvatinib resistance by facilitating EMT, cell migration, and invasion of LR HCC cells, indicating that LEF1 is a novel therapeutic target for overcoming acquired lenvatinib resistance.
Insights
Acquired resistance to lenvatinib in liver cancer (HCC) is driven by elevated lymphoid enhancer binding factor 1 (LEF1). Targeting LEF1 can restore sensitivity to lenvatinib, offering a new strategy against HCC treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
- Drug Resistance Mechanisms
Background:
- Acquired resistance to lenvatinib hinders treatment for unresectable hepatocellular carcinoma (HCC).
- Understanding resistance mechanisms is crucial for developing effective therapeutic strategies.
- Epithelial-mesenchymal transition (EMT), cell migration, and invasion are implicated in resistance.
Purpose of the Study:
- To investigate the molecular mechanisms underlying lenvatinib resistance in HCC.
- To identify novel therapeutic targets for overcoming acquired resistance.
- To evaluate the potential of targeting lymphoid enhancer binding factor 1 (LEF1) to restore lenvatinib sensitivity.
Main Methods:
- Established two lenvatinib-resistant (LR) HCC cell lines (Hep3B-LR, HepG2-LR) via gradient drug concentration.
- Performed RNA-sequencing and Gene Set Enrichment Analysis (GSEA) on LR and parental cells.
- Analyzed Gene Expression Omnibus (GEO) and The Cancer Genome Atlas Program (TCGA) databases.
- Utilized a small-molecule inhibitor (ICG001) and LEF1 knockdown to assess therapeutic effects.
Main Results:
- Lenvatinib treatment promoted EMT, cell migration, and invasion in HCC cells.
- GSEA revealed activation of the Wnt signaling pathway and elevated β-catenin and LEF1 in LR HCC cells.
- LEF1 was identified as a key regulator of EMT, linked to lenvatinib resistance and poor prognosis in HCC.
- Targeting LEF1 with ICG001 or knockdown resensitized LR HCC cells to lenvatinib.
Conclusions:
- Upregulation of LEF1 confers lenvatinib resistance in HCC by promoting EMT, migration, and invasion.
- LEF1 is a novel molecular target for overcoming acquired lenvatinib resistance in HCC.
- Targeting LEF1 presents a promising therapeutic strategy for patients with lenvatinib-resistant HCC.
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