Title | A novel role for microphthalmia-associated transcription factor-regulated pigment epithelium-derived factor during melanoma progression. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Dadras SS, Lin RJ, Razavi G, Kawakami A, Du J, Feige E, Milner DA, Loda MF, Granter SR, Detmar M, Widlund HR, Horstmann MA, Fisher DE |
Journal | Am J Pathol |
Volume | 185 |
Issue | 1 |
Pagination | 252-65 |
Date Published | 2015 Jan |
ISSN | 1525-2191 |
Keywords | Adult, Aged, Aged, 80 and over, Animals, Base Sequence, Cell Line, Tumor, Eye Proteins, Female, Gene Expression Regulation, Neoplastic, Gene Silencing, Humans, Immunohistochemistry, Male, Melanocytes, Melanoma, Mice, Microphthalmia-Associated Transcription Factor, Microscopy, Fluorescence, Middle Aged, Molecular Sequence Data, Neoplasm Invasiveness, Neoplasm Metastasis, Nerve Growth Factors, Oligonucleotide Array Sequence Analysis, Polymerase Chain Reaction, RNA, Small Interfering, Sequence Homology, Nucleic Acid, Serpins, Skin Neoplasms, Young Adult |
Abstract | Microphthalmia-associated transcription factor (MITF) acts via pigment epithelium-derived factor (PEDF), an antiangiogenic protein, to regulate retinal pigment epithelium migration. PEDF expression and/or regulation during melanoma development have not been investigated previously. Using immunohistochemistry, we determined expression of PEDF in common and dysplastic melanocytic nevi, melanoma in situ, invasive melanoma, and metastatic melanoma (n = 102). PEDF expression was consistently decreased in invasive and metastatic melanoma, compared with nevi and melanoma in situ (P < 0.0001). PEDF was lost in thicker melanomas (P = 0.003), and correlated with depth of invasion (P = 0.003) and distant metastasis (P = 0.0331), but only marginally with mitotic index, AJCC stage, nodal metastasis, or blood vascular density (0.05 < P < 0.10). Quantitative real-time PCR and microarray analyses confirmed PEDF down-regulation at the mRNA level in several melanoma lines, compared with melanocytes. MITF positively correlated with PEDF expression in invasive melanomas (P = 0.0003). Searching for PEDF regulatory mechanisms revealed two occupied conserved E-boxes (DNA recognition elements) in the first intron of the human and mouse PEDF promoter regions, confirmed by binding assays. Dominant-negative and siRNA approaches in vivo demonstrated direct transcriptional influence of MITF on PEDF, establishing the PEDF gene (SERPINF1) as a MITF target in melanocytes and melanoma cells. These findings suggest that loss of PEDF expression promotes early invasive melanoma growth. |
DOI | 10.1016/j.ajpath.2014.09.012 |
Alternate Journal | Am J Pathol |
PubMed ID | 25447045 |
PubMed Central ID | PMC4278358 |
Grant List | P01 CA163222 / CA / NCI NIH HHS / United States R01 AR043369 / AR / NIAMS NIH HHS / United States 1-P01-CA163222 / CA / NCI NIH HHS / United States R01-AR043369-17 / AR / NIAMS NIH HHS / United States |
Related Faculty:
Massimo Loda, M.D.