Dataset Information

BRAFV600E mutations in malignant melanoma are associated with increased expressions of BAALC.

ABSTRACT: UNLABELLED:BACHGROUND: Activating BRAF mutations are present in approximately 50% of melanomas. Although different downstream target genes of the most common mutant V600E have been identified, the contribution of activating BRAF mutations to malignant transformation needs further clarification. METHODS:Microarray gene analysis was performed for human melanoma cell lines harboring BRAFV600E mutations in comparison to cell lines without this mutation. RESULTS:This analysis revealed a more than two fold down-regulation of 43 and an increase of 39 gene products. BAALC (Brain and acute Leukaemia, cytoplasmatic) was most prominently regulated, since it was up-regulated in mutated cell lines by a mean of 11.45. Real time PCR analyses with RNA from melanoma cell lines (n = 30) confirmed the BRAF-activation dependent up-regulation of BAALC. CONCLUSION:BAALC, which has been associated with cell dedifferentiation and migration, may function as a downstream effector of activating BRAF mutations during melanomagenesis.

SUBMITTER: Schrama D

PROVIDER: S-EPMC2483271 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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BRAFV600E mutations in malignant melanoma are associated with increased expressions of BAALC.

Schrama David D Keller Gunhild G Houben Roland R Ziegler Christian G CG Vetter-Kauczok Claudia S CS Ugurel Selma S Becker Jürgen C JC

Journal of carcinogenesis 20080716

<h4>Unlabelled</h4>BACHGROUND: Activating BRAF mutations are present in approximately 50% of melanomas. Although different downstream target genes of the most common mutant V600E have been identified, the contribution of activating BRAF mutations to malignant transformation needs further clarification.<h4>Methods</h4>Microarray gene analysis was performed for human melanoma cell lines harboring BRAFV600E mutations in comparison to cell lines without this mutation.<h4>Results</h4>This analysis re ...[more]

PMID: 18631381

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Project description:Previously, we have demonstrated that nuclear BRAFV600E is associated with melanoma aggressiveness and vemurafenib resistance. However, the underlying mechanisms of how nuclear localization of BRAFV600E promotes cell aggressiveness have not yet been investigated. Despite therapeutic advancements targeting cutaneous melanoma, unknown cellular processes prevent effective treatment for this malignancy, prompting an urgent need to identify new biological targets. This study aims to explore the association of inducible heme oxygenase 1 (HMOX-1) with nuclear BRAFV600E in promoting melanoma aggressiveness. Proteomics analysis was performed to identify the interacting partner(s) of nuclear BRAFV600E. Immunohistochemistry was applied to evaluate the levels of HMOX-1 and nuclear BRAFV600E expression in melanoma and adjacent healthy tissues. Immunofluorescence assessed the nuclear localization of BRAFV600E in vemurafenib-resistant A375R melanoma cells. Further study of HMOX-1 knockdown or BRAFV600E overexpression in melanoma cells suggested a role for HMOX-1 in the regulation of cell proliferation in vivo and in vitro. Finally, Western blot analysis was performed to confirm the pathway by which HMOX-1 mediates Akt signaling. Proteomics results showed that HMOX-1 protein expression was 10-fold higher in resistant A375R cells compared to parental counterpart cells. In vitro and in vivo results illustrate that nuclear BRAFV600E promotes HMOX-1 overexpression, whereas HMOX-1 reduction represses melanoma cell proliferation and tumor growth. Mechanistic studies revealed that HMOX-1 was associated with nuclear BRAFV600E localization, thus promoting melanoma proliferation via a persistent activation of the AKT pathway. Our results highlight a previously unknown mechanism in which the nuclear BRAFV600E/HMOX-1/AKT axis plays an essential role in melanoma cell proliferation. Targeting HMOX-1 could be a novel method for treating melanoma patients who develop BRAF inhibitor resistance.

Dataset Information

BRAFV600E mutations in malignant melanoma are associated with increased expressions of BAALC.

Publications

BRAFV600E mutations in malignant melanoma are associated with increased expressions of BAALC.

Similar Datasets

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