RRC ID 12749
Author Kido K, Sumimoto H, Asada S, Okada SM, Yaguchi T, Kawamura N, Miyagishi M, Saida T, Kawakami Y.
Title Simultaneous suppression of MITF and BRAF V600E enhanced inhibition of melanoma cell proliferation.
Journal Cancer Sci
Abstract Microphthalmia-associated transcription factor (MITF) is a master gene regulating differentiation of melanocytes, and a lineage survival oncogene mediating pro-proliferative function in malignant melanoma. However, high expression of MITF also has an anti-proliferative effect. To clarify the therapeutic implication of MITF as a molecular target for human melanoma, we evaluated the role of MITF in cell proliferation in a panel of human melanoma cell lines which express different levels of MITF. We found that both MITF depletion and forced expression of MITF significantly inhibited proliferation, suggesting that endogenous MITF is regulated at an appropriate level for melanoma cell proliferation, and could be a molecular target for melanoma. However, half of the melanoma cell lines in this study were relatively resistant to MITF depletion, indicating other treatment strategies are required for therapy. Our microarray analysis indicated that regulation of several cell growth-associated molecules may be independent of MITF and dependent on BRAF(V600E). Thus to enhance the anti-proliferative effect of MITF down-regulation, we combined shRNA-mediated MITF depletion with BRAF(V600E) inactivation, another known molecular target for melanoma. Indeed, simultaneous depletion of both MITF and BRAF(V600E) significantly inhibited melanoma growth even for the melanoma cell lines resistant to MITF depletion. These results suggest MITF may be an important molecular target for human melanoma and simultaneous inhibition of MITF and MAPK signaling may be an attractive strategy for melanoma treatment.
Volume 100(10)
Pages 1863-9
Published 2009-10-1
DOI 10.1111/j.1349-7006.2009.01266.x
PMID 19659611
MeSH Blotting, Western Cell Line, Tumor Cell Proliferation Gene Expression Profiling Gene Expression Regulation, Neoplastic* Humans Melanoma / genetics Melanoma / metabolism* Microphthalmia-Associated Transcription Factor / genetics Microphthalmia-Associated Transcription Factor / metabolism* Oligonucleotide Array Sequence Analysis Proto-Oncogene Proteins B-raf / genetics Proto-Oncogene Proteins B-raf / metabolism* Signal Transduction / physiology
IF 4.966
Times Cited 24
DNA material pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393)