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Tang Q , Lento A , Suzuki K , Efe G , Karakasheva T , Long A , Giroux V , Islam M , Wileyto EP , Klein-Szanto AJ , Nakagawa H , Bass A , Rustgi AK
Rab11-FIP1 mediates epithelial-mesenchymal transition and invasion in esophageal cancer
EMBO Rep. 2021 Feb 3;22(2) :e48351
PMID: 33403789    PMCID: PMC7857540    URL: https://www.ncbi.nlm.nih.gov/pubmed/33403789
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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.
Notes
Tang, Qiaosi Lento, Ashley Suzuki, Kensuke Efe, Gizem Karakasheva, Tatiana Long, Apple Giroux, Veronique Islam, Mirazul Wileyto, E Paul Klein-Szanto, Andres J Nakagawa, Hiroshi Bass, Adam Rustgi, Anil K eng P01 CA098101/CA/NCI NIH HHS/ American Cancer Society (ACS) P01-CA098101/HHS | NIH | National Cancer Institute (NCI) P30-CA01369645/HHS | NIH | National Cancer Institute (NCI) England EMBO Rep. 2021 Feb 3;22(2):e48351. doi: 10.15252/embr.201948351. Epub 2021 Jan 6.