Loss of MTA2‐mediated downregulation of PTK7 inhibits hepatocellular carcinoma metastasis progression by modulating the FAK‐MMP7 axis

• Published in: Environmental toxicology 2024-04, Vol.39 (4), p.1897-1908
• Main Authors: Hu, Huang‐Ming, Lee, Hsiang‐Lin, Liu, Chung‐Jung, Hsieh, Yi‐Hsien, Chen, Yong‐Syuan, Hsueh, Kuan‐Chun
• Format: Article
• Language: English
• Subjects: Cancer; Carcinoma, Hepatocellular - pathology; Cell Adhesion Molecules - metabolism; Cell Line, Tumor; Cell Movement - genetics; Cells; Correlation; Down-Regulation; Focal adhesion kinase; Gene expression; Gene Expression Regulation, Neoplastic; Genomes; Hepatocellular carcinoma; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; invasion; Kinases; Liver cancer; Liver Neoplasms - pathology; Matrilysin; Matrix metalloproteinase; matrix metalloproteinase 7; Matrix Metalloproteinase 7 - genetics; Matrix Metalloproteinase 7 - metabolism; Matrix metalloproteinases; Metalloproteinase; Metastases; Metastasis; metastasis tumor‐associated protein‐2; migration; Neoplasm Invasiveness - genetics; Neoplasm Proteins - genetics; Neoplasms; protein tyrosine kinase 7; Protein-tyrosine kinase; Proteins; Receptor Protein-Tyrosine Kinases - genetics; Recombinants; Repressor Proteins; Survival; Tumors; Tyrosine
• ISSN: 1520-4081; 1522-7278
• DOI: 10.1002/tox.24073

The expression of metastasis tumor‐associated protein 2 (MTA2) and protein tyrosine kinase 7 (PTK7) is associated with hepatocellular carcinoma (HCC) progression. However, the functional effect and mechanism through which MTA2 regulates PTK7‐mediated HCC progression remains unclear. Here, we found that MTA2 knockdown significantly down‐regulated PTK7 expression in HCC cells (SK‐Hep‐1 and PLC/PRF/5). Data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases show that the PTK7 expression level was higher in HCC tissues than in normal liver tissues. In HCC patients, the PTK7 expression level clearly correlated with tumor stage and grade, lower overall survival (OS) correlated positively with MTA2 level, and PTK7 expression acted as a downstream factor for MTA2 expression. In addition, matrix metalloproteinase 7 (MMP7) expression was closely regulated by PTK7, and the mRNA and protein expression levels of MTA2 and PTK7 correlated positively with lower OS. MMP7 downregulation by PTK7 knockdown clearly decreased the migration and invasion abilities of HCC cells. In HCC cells, recombinant human MMP7 reversed the PTK7 knockdown‐induced suppression of migration and invasion. Furthermore, deactivation of FAK using siFAK or FAK inhibitor (PF‐573228, PF) synergistically contributed to PTK7 knockdown‐inhibited FAK activity, MMP7 expression, and the migration and invasion abilities of HCC cells. Collectively, our findings show that PTK7 mediates HCC progression by regulating the MTA2‐FAK‐MMP7 axis and may be a diagnostic value for HCC patients.