Abstract
Esophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer worldwide. The most commonly mutated gene in ESCC is TP53. Using a combinatorial genetic and carcinogenic approach, we generate a novel mouse model of ESCC expressing either mutant or null p53 and show that mutant p53 exhibits enhanced tumorigenic properties and displays a distinct genomic profile. Through RNA-seq analysis, we identify several endocytic recycling genes, including Rab Coupling Protein (Rab11-FIP1), which are significantly downregulated in mutant p53 tumor cells. In 3-dimensional (3D) organoid models, genetic knockdown of Rab11-FIP1 results in increased organoid size. Loss of Rab11-FIP1 increases tumor cell invasion in part through mutant p53 but also in an independent manner. Furthermore, loss of Rab11-FIP1 in human ESCC cell lines decreases E-cadherin expression and increases mesenchymal lineage-specific markers, suggesting induction of epithelial-mesenchymal transition (EMT). Rab11-FIP1 regulates EMT through direct inhibition of Zeb1, a key EMT transcriptional factor. Our novel findings reveal that Rab11-FIP1 regulates organoid formation, tumor cell invasion, and EMT.
Original language | American English |
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Article number | e48351 |
Pages (from-to) | e48351 |
Journal | EMBO Reports |
Volume | 22 |
Issue number | 2 |
DOIs | |
State | Published - Feb 3 2021 |
Externally published | Yes |
Keywords
- *Carcinoma, Squamous Cell/genetics Cell Line, Tumor Cell Movement/genetics Cell Proliferation Epithelial-Mesenchymal Transition/genetics *Esophageal Neoplasms/genetics *Esophageal Squamous Cell Carcinoma/genetics Gene Expression Regulation, Neoplastic Humans Neoplasm Invasiveness Epithelial-Mesenchymal transition Rab coupling protein (Rab11-FIP1) esophageal cancer invasion
- Cell Movement/genetics
- Carcinoma, Squamous Cell/genetics
- Cell Proliferation
- Epithelial-Mesenchymal Transition/genetics
- Esophageal Neoplasms/genetics
- Neoplasm Invasiveness
- Humans
- Gene Expression Regulation, Neoplastic
- Cell Line, Tumor
- Esophageal Squamous Cell Carcinoma/genetics
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