Role of pelitinib in the regulation of migration and invasion of hepatocellular carcinoma cells via inhibition of Twist1

• Published in: BMC cancer 2023-07, Vol.23 (1), p.703-703, Article 703
• Main Authors: Lee, Sewoong, Kang, Eunjeong, Lee, Unju, Cho, Sayeon
• Format: Article
• Language: English
• Subjects: Akt; AKT protein; Analysis; Antibodies; Antitumor agents; Bioinformatics; Cancer therapies; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Care and treatment; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell viability; Clinical trials; Cytotoxicity; Development and progression; DNA binding proteins; Down-regulation; E-cadherin; Epidermal growth factor; Epithelial-mesenchymal transition; Epithelial-Mesenchymal Transition - genetics; Federal regulation; Gelatin; Gelatinase A; Gene Expression Regulation, Neoplastic; HCC; Hepatocellular carcinoma; Hepatoma; Humans; Immunoblotting; Kinases; Life sciences; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Lung cancer; MAP kinase; MAPK; Medical prognosis; Metalloproteinase; Metastases; Metastasis; Mitogen-activated protein kinases; N-Cadherin; Neoplasm Invasiveness - genetics; Pelitinib; Polymerase chain reaction; Prevention; Protein kinases; Protein-tyrosine kinase receptors; Proto-Oncogene Proteins c-akt - metabolism; Risk factors; Scientific equipment and supplies industry; Signal transduction; siRNA; Statistical analysis; Stem cells; Transcription factors; Twist1; Tyrosine; Wound healing
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-023-11217-2

Overexpression of Twist1, one of the epithelial-mesenchymal transition-transcription factors (EMT-TFs), is associated with hepatocellular carcinoma (HCC) metastasis. Pelitinib is known to be an irreversible epidermal growth factor receptor tyrosine kinase inhibitor that is used in clinical trials for colorectal and lung cancers, but the role of pelitinib in cancer metastasis has not been studied. This study aimed to investigate the anti-migration and anti-invasion activities of pelitinib in HCC cell lines. Using three HCC cell lines (Huh7, Hep3B, and SNU449 cells), the effects of pelitinib on cell cytotoxicity, invasion, and migration were determined by cell viability, wound healing, transwell invasion, and spheroid invasion assays. The activities of MMP-2 and -9 were examined through gelatin zymography. Through immunoblotting analyses, the expression levels of EMT-TFs (Snail1, Twist1, and ZEB1) and EMT-related signaling pathways such as mitogen-activated protein kinases (MAPKs) and Akt signaling pathways were measured. The activity and expression levels of target genes were analyzed by reporter assay, RT-PCR, quantitative RT-PCR, and immunoblotting analysis. Statistical analysis was performed using one-way ANOVA with Dunnett's Multiple comparison tests in Prism 3.0 to assess differences between experimental conditions. In this study, pelitinib treatment significantly inhibited wound closure in various HCC cell lines, including Huh7, Hep3B, and SNU449. Additionally, pelitinib was found to inhibit multicellular cancer spheroid invasion and metalloprotease activities in Huh7 cells. Further investigation revealed that pelitinib treatment inhibited the migration and invasion of Huh7 cells by inducing Twist1 degradation through the inhibition of MAPK and Akt signaling pathways. We also confirmed that the inhibition of cell motility by Twist1 siRNA was similar to that observed in pelitinib-treated group. Furthermore, pelitinib treatment regulated the expression of target genes associated with EMT, as demonstrated by the upregulation of E-cadherin and downregulation of N-cadherin. Based on our novel finding of pelitinib from the perspective of EMT, pelitinib has the ability to inhibit EMT activity of HCC cells via inhibition of Twist1, and this may be the potential mechanism of pelitinib on the suppression of migration and invasion of HCC cells. Therefore, pelitinib could be developed as a potential anti-cancer drug for HCC.