overexpression leads to lenvatinib resistance in hepatocellular carcinoma.

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 () 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 expression was observed in lenvatinib-resistant (LR) cell lines and HCC tissues, whereas low expression inhibited the proliferation of HCC cells. Circulating microRNA 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, may serve as a candidate therapeutic target for LR liver cancer patients.