Roles of ZEB1 and ZEB2 in E‐cadherin expression and cell aggressiveness in head and neck cancer

• Published in: Genes to cells : devoted to molecular & cellular mechanisms 2024-12, Vol.29 (12), p.1131-1143
• Main Authors: Kinouchi, Arisa, Jubashi, Takahiro, Tatsuno, Rikito, Ichikawa, Jiro, Sakamoto, Kaname, Sakurai, Daiju, Kawasaki, Tomonori, Ishii, Hiroki, Miyazawa, Keiji, Saitoh, Masao
• Format: Article
• Language: English
• Subjects: Animals; Cadherins - genetics; Cadherins - metabolism; Cancer; Cell differentiation; Cell Line, Tumor; Cell Movement; Chemoresistance; Conformation; EMT; Gene Expression Regulation, Neoplastic; Head & neck cancer; Head and neck carcinoma; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; head and neck squamous cell carcinoma; Homeobox; Humans; Metastases; Mice; Mice, Inbred C57BL; Molecular modelling; Original; Phenotypes; Squamous cell carcinoma; ZEB1; ZEB2; Zinc Finger E-box Binding Homeobox 2 - genetics; Zinc Finger E-box Binding Homeobox 2 - metabolism; Zinc Finger E-box-Binding Homeobox 1 - genetics; Zinc Finger E-box-Binding Homeobox 1 - metabolism; Zinc finger proteins
• ISSN: 1356-9597; 1365-2443; 1365-2443
• DOI: 10.1111/gtc.13167

Zinc finger E‐box binding homeobox 1 (ZEB1) has been identified as a key factor in cancer cell differentiation and metastasis, and has been well studied in the field of cancer cell biology. ZEB2 has a highly similar conformation to ZEB1, but its role in head and neck squamous cell carcinoma (HNSCC) cells is not fully understood. Here, we separately overexpressed ZEB1 and ZEB2 in C57BL/6 mouse oral cancer (MOC) cells and investigated their cellular characteristics, including E‐cadherin levels, motile properties, chemoresistance, and metastatic ability in immunocompetent mice. Both ZEB1 and ZEB2 overexpression reduced epithelial traits and converted cells to an aggressive phenotype. Surprisingly, ZEB1 overexpression increased the endogenous level of ZEB2 in MOC cells, and vice versa. The molecular mechanisms underlying these findings remain unclear. However, the in vitro anchorage‐independent growth of MOC cells overexpressing ZEB2 was considerably greater than that of MOC cells overexpressing ZEB1. These findings suggest that ZEB2, like ZEB1, has the ability to induce the differentiation of cancer cells into those with highly aggressive traits. A two‐well silicone insert for cell co‐cultivation was used because this method makes it possible to obtain photos of the two cell types simultaneously after immunostaining, with subsequent comparison of their protein expression levels. After MOC1 and MOC1‐ZEB1 cells were seeded separately in two‐well silicone inserts, actin cytoskeleton reorganization was visualized by tetramethyl rhodamine isothiocyanate (TRITC)‐phalloidin staining.