Hypoxia activates cadherin-22 synthesis via eIF4E2 to drive cancer cell migration, invasion and adhesion
| Autor: | James Uniacke, Erin J. Specker, Joseph Varga, Brenda L. Coomber, N J Kelly, C M Romeo |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Breast Neoplasms Biology Mechanistic Target of Rapamycin Complex 1 Article Metastasis 03 medical and health sciences Downregulation and upregulation Antigens CD Cell Movement Glioma Cell Line Tumor Spheroids Cellular Genetics medicine Cell Adhesion Gene silencing Humans Neoplasm Invasiveness RNA Messenger RNA Small Interfering Molecular Biology Neoplasm Staging Cadherin Carcinoma Ductal Breast Hypoxia (medical) medicine.disease Cadherins Cell Hypoxia Up-Regulation Gene Expression Regulation Neoplastic 030104 developmental biology Eukaryotic Initiation Factor-4E Tumor progression RNA Cap-Binding Proteins Gene Knockdown Techniques Cancer cell Cancer research Disease Progression Female medicine.symptom Neoplasm Grading |
| Zdroj: | Oncogene. 37(5) |
| ISSN: | 1476-5594 |
| Popis: | Hypoxia is a driver of cell movement in processes such as development and tumor progression. The cellular response to hypoxia involves a transcriptional program mediated by hypoxia-inducible factors, but translational control has emerged as a significant contributor. In this study, we demonstrate that a cell–cell adhesion molecule, cadherin-22, is upregulated in hypoxia via mTORC1-independent translational control by the initiation factor eIF4E2. We identify new functions of cadherin-22 as a hypoxia-specific cell-surface molecule involved in cancer cell migration, invasion and adhesion. Silencing eIF4E2 or cadherin-22 significantly impaired MDA-MB-231 breast carcinoma and U87MG glioblastoma cell migration and invasion only in hypoxia, while reintroduction of the respective exogenous gene restored the normal phenotype. Cadherin-22 was evenly distributed throughout spheroids and required for their formation and support of a hypoxic core. Conversely, E-cadherin translation was repressed by hypoxia and only expressed in the oxygenated cells of U87MG spheroids. Furthermore, immunofluorescence on paraffin-embedded human tissue from 40 glioma and 40 invasive ductal breast carcinoma patient specimens revealed that cadherin-22 expression colocalized with areas of hypoxia and significantly correlated with tumor grade and progression-free survival or stage and tumor size, respectively. This study broadens our understanding of tumor progression and metastasis by highlighting cadherin-22 as a potential new target of cancer therapy to disable hypoxic cancer cell motility and adhesion. |
| Databáze: | OpenAIRE |
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