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AKR1C1 overexpression leads to lenvatinib resistance in hepatocellular carcinoma
Cheng Gao1, Liang Chang1, Tianxin Xu1
1Department of General Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.
Background:
Lenvatinib is an orally administered drug that works as a multi-targeted tyrosine kinase inhibitor. It has been approved as a first-line drug after sorafenib in hepatocellular carcinoma (HCC). However, little is currently known about its treatment, targets, and possible resistance in HCC.
Methods:
The proliferation of HCC cells was evaluated using colony formation, 5-ethynyl-2'-deoxyuridine (EDU), wound healing, cell counting kit-8 (CCK-8), and xenograft tumor assays. RNA sequencing (RNA-seq) was utilized to comprehensively examine variations in highly metastatic human liver cancer cells (MHCC-97H) cells (treated with various doses of lenvatinib) at the transcriptomic level. Protein interactions and functions were predicted using Cytoscape-generated networks and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, while the proportions of 22 immune cell types were examined with CIBERSORT. Aldo-keto reductase family 1 member C1 (AKR1C1) expression was verified by quantitative real time polymerase chain reaction (qRT-PCR) or immunohistochemistry in HCC cells and liver tissues. Micro ribonucleic acid (miRNAs) were predicted using online tools and potential drugs were screened using the Genomics of Drug Sensitivity in Cancer (GDSC) database.
Results:
Lenvatinib inhibited the proliferation of HCC cells. The obtained results suggested that an elevated level of AKR1C1 expression was observed in lenvatinib-resistant (LR) cell lines and HCC tissues, whereas low AKR1C1 expression inhibited the proliferation of HCC cells. Circulating microRNA 4644 (miR-4644) was predicted to serve as a promising biomarker for the early diagnosis of lenvatinib resistance. Online data analysis of LR cells showed significant differences in the immune microenvironment and drug sensitivity compared with their parental counterparts.
Conclusions:
Taken together, AKR1C1 may serve as a candidate therapeutic target for LR liver cancer patients.
Insights
Lenvatinib inhibits hepatocellular carcinoma (HCC) cell proliferation. Elevated Aldo-keto reductase family 1 member C1 (AKR1C1) expression is linked to lenvatinib resistance, suggesting AKR1C1 as a potential therapeutic target for liver cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Lenvatinib is an approved multi-targeted tyrosine kinase inhibitor for hepatocellular carcinoma (HCC).
- Understanding lenvatinib's targets and resistance mechanisms in HCC is crucial for optimizing treatment.
- Current knowledge regarding lenvatinib resistance in HCC is limited.
Purpose of the Study:
- To investigate the molecular mechanisms underlying lenvatinib resistance in HCC.
- To identify potential therapeutic targets for overcoming lenvatinib resistance.
- To explore the role of AKR1C1 and miR-4644 in lenvatinib-treated HCC.
Main Methods:
- Cell proliferation assays (colony formation, EDU, wound healing, CCK-8) and xenograft tumor models were used.
- RNA sequencing (RNA-seq) analyzed transcriptomic changes in lenvatinib-treated HCC cells.
- Bioinformatic analyses predicted protein interactions, KEGG pathways, immune cell proportions (CIBERSORT), and miRNA targets.
Main Results:
- Lenvatinib treatment inhibited HCC cell proliferation.
- Increased AKR1C1 expression was observed in lenvatinib-resistant (LR) HCC cell lines and tissues.
- MicroRNA 4644 (miR-4644) was identified as a potential biomarker for early lenvatinib resistance detection.
Conclusions:
- AKR1C1 may represent a novel therapeutic target for patients with lenvatinib-resistant HCC.
- Significant alterations in the immune microenvironment and drug sensitivity were noted in LR cells.
- Further research into AKR1C1 and miR-4644 could lead to improved HCC treatment strategies.
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