Loss of Sh3gl2/Endophilin A1 Is a Common Event in Urothelial Carcinoma that Promotes Malignant Behavior
| Autor: | Rosalyn M. Adam, Jonathan M. Dreyfuss, Dolores Di Vizio, Peter J. Park, Martin H. Hager, Joaquim Bellmunt, Shyama Majumdar, Jonathan E. Rosenberg, Robert J. Matusik, Edward M. Gong, David J. DeGraff |
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| Rok vydání: | 2013 |
| Předmět: |
STAT3 Transcription Factor
Cancer Research medicine.disease_cause lcsh:RC254-282 Receptor tyrosine kinase Mice Cell Movement Cell Line Tumor medicine Animals Humans Gene silencing Gene Silencing Epidermal growth factor receptor STAT3 Adaptor Proteins Signal Transducing Cell Proliferation biology Cell growth Gene Expression Profiling Carcinoma lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Xenograft Model Antitumor Assays Tumor Burden ErbB Receptors Cell Transformation Neoplastic src-Family Kinases Urinary Bladder Neoplasms Tumor progression Disease Progression biology.protein Cancer research Signal transduction Carcinogenesis Signal Transduction Research Article |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 15, Iss 7, Pp 749-760 (2013) |
| ISSN: | 1476-5586 |
| DOI: | 10.1593/neo.121956 |
| Popis: | Urothelial carcinoma (UC) causes substantial morbidity and mortality worldwide. However, the molecular mechanisms underlying urothelial cancer development and tumor progression are still largely unknown. Using informatics analysis, we identified Sh3gl2 (endophilin A1) as a bladder urothelium-enriched transcript. The gene encoding Sh3gl2 is located on chromosome 9p, a region frequently altered in UC. Sh3gl2 is known to regulate endocytosis of receptor tyrosine kinases implicated in oncogenesis, such as the epidermal growth factor receptor (EGFR) and c-Met. However, its role in UC pathogenesis is unknown. Informatics analysis of expression profiles as well as immunohistochemical staining of tissue microarrays revealed Sh3gl2 expression to be decreased in UC specimens compared to nontumor tissues. Loss of Sh3gl2 was associated with increasing tumor grade and with muscle invasion, which is a reliable predictor of metastatic disease and cancer-derived mortality. Sh3gl2 expression was undetectable in 19 of 20 human UC cell lines but preserved in the low-grade cell line RT4. Stable silencing of Sh3gl2 in RT4 cells by RNA interference 1) enhanced proliferation and colony formation in vitro, 2) inhibited EGF-induced EGFR internalization and increased EGFR activation, 3) stimulated phosphorylation of Src family kinases and STAT3, and 4) promoted growth of RT4 xenografts in subrenal capsule tissue recombination experiments. Conversely, forced re-expression of Sh3gl2 in T24 cells and silenced RT4 clones attenuated oncogenic behaviors, including growth and migration. Together, these findings identify loss of Sh3gl2 as a frequent event in UC development that promotes disease progression. |
| Databáze: | OpenAIRE |
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