This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Niu, G. Articles by Yu, H. PubMed PubMed Citation Articles by Niu, G. Articles by Yu, H.

---

Angiogenesis, Metastasis, and the Cellular Microenvironment

Signal Transducer and Activator of Transcription 3 Is Required for Hypoxia-Inducible Factor-1 RNA Expression in Both Tumor Cells and Tumor-Associated Myeloid Cells

¹ H. Lee Moffitt Cancer Center and Research Institute, Department of Oncology, University of South Florida College of Medicine and ² College of Public Health, University of South Florida, Tampa, Florida; and ³ Beckman Research Institute, City of Hope National Medical Center, Duarte, California

Requests for reprints: Hua Yu, Beckman Research Institute, Room 1027, City of Hope Shapiro Building, 1500 East Duarte Road, Duarte, CA 91010-3000. Phone: 626-256-4673-63365; Fax: 626-256-8708. E-mail: hyu{at}coh.org

Hypoxia-inducible factor 1 (HIF-1) is a potent tumorigenic factor. Its subunit (HIF-1), which is tightly regulated in normal tissues, is elevated in tumors due to hypoxia and overactive growth signaling pathways. Although much is known about HIF-1 regulation in cancer cells, crucial molecular targets that affect HIF-1 levels modulated by both hypoxia and oncogenic signaling pathways remain to be identified. Additionally, whether and how the tumor microenvironment contributes to HIF-1 accumulation is unclear. This study shows a novel mechanism by which HIF-1 availability is regulated in both cancer cells and in myeloid cells in the tumor microenvironment. We show a requirement of signal transducer and activator of transcription 3 (Stat3) for HIF-1 RNA expression under both hypoxia and growth signaling conditions. Furthermore, tumor-derived myeloid cells express elevated levels of HIF-1 mRNA relative to their counterparts from normal tissues in a Stat3-dependent manner. Additionally, Stat3 activity in the nontransformed cells in the tumor milieu affects HIF-1 RNA expression of the entire growing tumor. Consistent with a role of Stat3 in regulating HIF-1 RNA transcription, elevated Stat3 activity increases HIF-1 promoter activity, and Stat3 protein binds to the HIF-1 promoter in both transformed cells and in growing tumors. Taken together, these findings show a novel mode by which HIF-1 is regulated not only in cancer cells but also in the tumor-associated inflammatory cells, suggesting Stat3 as an important molecular target for inhibiting the oncogenic potential of HIF-1 induced by both hypoxia and overactive growth signaling pathways prevalent in cancer. (Mol Cancer Res 2008;6(7):1099–105)