This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kumar, S. M. Articles by Xu, X. Search for Related Content PubMed PubMed Citation Articles by Kumar, S. M. Articles by Xu, X.

Mutant V600E BRAF Increases Hypoxia Inducible Factor-1 Expression in Melanoma

¹ Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine and ² The Wistar Institute, Philadelphia, Pennsylvania

Requests for reprints: Xiaowei Xu, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104. Phone: 215-662-6503; Fax: 215-349-5910; E-mail: xug{at}mail.med.upenn.edu.

Mutations in the BRAF serine/threonine kinase gene are frequently found in cutaneous melanomas. Activation of hypoxia inducible factor-1 (HIF-1) in response to both hypoxic stress and oncogenic signals has important implications in cancer development and progression. Here, we report that mutant BRAF^V600E increases HIF-1 expression in melanoma cells. Our microarray profiling data in 35 melanoma and melanocyte cell lines showed that HIF-1 gene expression was significantly increased in melanomas harboring BRAF^V600E mutation. Stable suppression of mutant BRAF^V600E or both wild-type and mutant BRAF^V600E by RNA interference in melanoma cells resulted in significantly decreased HIF-1 expression. Knockdown of mutant BRAF^V600E induced significant reduction of cell survival and proliferation under hypoxic conditions, whereas knockdown of both wild-type and mutant BRAF^V600E resulted in further reduction. The effects of BRAF knockdown can be rescued by reintroducing BRAF^V600E into tumor cells. Transfection of BRAF^V600E into melanoma cells with wild-type BRAF induced significantly more hypoxic tolerance. Knockdown of HIF-1 in melanoma cells resulted in decreased cell survival under hypoxic conditions. Pharmacologic inhibition of BRAF by BAY 43-9006 also resulted in decreased HIF-1 expression. Although HIF-1 translational rate was not changed, the protein was less stable in BRAF knockdown cells. In additional, von Hippel-Lindau protein expression was significantly increased in BRAF knockdown cells. Our data show for the first time that BRAF^V600E mutation increases HIF-1 expression and melanoma cell survival under hypoxic conditions and suggest that effects of the oncogenic V600E BRAF mutation may be partially mediated through the HIF-1 pathway. [Cancer Res 2007;67(7):3177–84]

This article has been cited by other articles:

				H. Kikuchi, M. S. Pino, M. Zeng, S. Shirasawa, and D. C. Chung Oncogenic KRAS and BRAF Differentially Regulate Hypoxia-Inducible Factor-1{alpha} and -2{alpha} in Colon Cancer Cancer Res., November 1, 2009; 69(21): 8499 - 8506. [Abstract] [Full Text] [PDF]

				H. Yu, R. McDaid, J. Lee, P. Possik, L. Li, S. M. Kumar, D. E. Elder, P. Van Belle, P. Gimotty, M. Guerra, et al. The Role of BRAF Mutation and p53 Inactivation during Transformation of a Subpopulation of Primary Human Melanocytes Am. J. Pathol., June 1, 2009; 174(6): 2367 - 2377. [Abstract] [Full Text] [PDF]