Role of microphthalmia transcription factor (Mitf) in melanoma differentiation.
We transfected the melanocyte-specific Mitf-M isoform into the aggressive melanoma UISO-Mel-6 cell lines. Our data show that Mitf decreases cell proliferation and results in cells which grow in clusters. By analyzing the expression of the markers of differentiation, we demonstrate that Mitf favored increased expression of tyrosinase and tyrosinase-related protein-1. In addition, Mitf induces Bcl-2 expression following transfection of UISO-Mel-6 cells. We also showed that Mitf gene affects cell-cycle distribution by resting cells preferentially in G2/G1 phase, and inducing the expression of p21 and p27. Moreover, we performed in vivo studies using subcutaneous injection of UISO-Mel-6 and UISO-Mel-6-Mitf in Balb/c nude mice. Our data show that Mitf inhibits tumor growth and decreases Ki67 expression. Tumors induced by UISO-Mel-6 cells were ulcerated and resulted in metastases to liver. None of the mice injected with UISO-Mel-6(Mitf+) cells harbored liver metastases. Our results suggest that Mitf is involved in melanoma differentiation and leads to a less aggressive phenotype.
Lekmine
Fatima
F
Department of Surgical Oncology, University of Illinois at Chicago, 840 South Wood Street, M/C 820, Chicago, IL 60612, USA. fatimal@uic.edu
Chang
C K
CK
Sethakorn
Nan
N
Das Gupta
Tapas K
TK
Salti
George I
GI
D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D018450:Disease Progression; D016193:G1 Phase / Q000235:genetics / Q000502:physiology; D016195:G2 Phase / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D008113:Liver Neoplasms / Q000556:secondary; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000502:physiology*; D009362:Neoplasm Metastasis / Q000473:pathology; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D051739:Microphthalmia-Associated Transcription Factor; D019253:Proto-Oncogene Proteins c-bcl-2; D010088:Oxidoreductases; C064056:tyrosinase-related protein-1