Functional Oct4B induction by hypoxia promotes lung cancer oncogenesis and epithelial-mesenchymal trans-differentiation
| Autor: | Chih-Hung Chung, 鍾志宏 |
|---|---|
| Rok vydání: | 2010 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 98 Hypoxia, a reduction of normal oxygen levels in cells or tissues, creates a variety of changes in cell metabolism including increased oxidative stress and DNA damage. Though Oct4, a homeobox transcription factor essential for self-renewal of stem cells, is expressed in various cancers, little is known about the functional role of Oct4 in tumorigenesis. In this study, we discovered that hypoxia induces a short isoform of Oct4, termed as Oct4B, in lung cancer through a HIF-2? dependent pathway. Overexpression of Oct4B induced cell proliferation and anchorage-independent growth of lung cancer, indicating the oncogenic potential of Oct4B. In addition, ectopic expression of Oct4B prevented cells from oxidative stress induced apoptosis, suggesting a functional role of Oct4B in anti-apoptosis. Overexpression of Oct4B promoted tumor formation in xenograft mouse model, demonstrating the positive involvement of Oct4B in tumorigenesis. We observed the increased activity of EGFR signaling in both hypoxia-treated or Oct4B-transfected cells. Q-PCR analysis demonstrated that Oct4B enhanced the transcript of TGF-?? a cognate ligand of EGFR. In addition, ectopic expression of Oct4B induced epithelial mesenchymal tans-differentiation and promoted cell migration. Through cDNA microarray and Q-PCR analyses, we identified that Oct4B induces Slug, a key effector in epithelial mesenchymal tans-differentiation.Thus, our results provide a novel mechanism that shows how Oct4B is induced by hypoxia to enable cancer cells to adapt environmental pressures and encourage malignancy in lung cancer |
| Databáze: | Networked Digital Library of Theses & Dissertations |
| Externí odkaz: |
|