The molecular changes associated with the transition of melanoma cells from radial growth phase (RGP) to vertical growth phase (VGP) (metastatic phenotype) are not very well defined. Recent work from this laboratory demonstrated that the expression of the cell surface adhesion molecule MCAM/MUC18, which belongs to the immunoglobulin superfamily, directly correlates with the metastatic potential of human melanoma cells. While none of the MCAM/MUC18-negative cell lines examined have been found to be metastatic, transfection of such cells with MCAM/MUC18 gene rendered them metastatic in nude mice. In addition, we have recently demonstrated that the progression of melanoma is associated with loss of expression of the c-KIT proto-oncogene tyrosine kinase receptor. Furthermore, re-expression of the c-KIT receptor in highly metastatic cell lines inhibited their tumorigenicity and metastatic potential in nude mice. Indeed, exposure of c-KIT-positive melanoma cells in vitro and in vivo to stem cell factor (SCF), the ligand for c-KIT, triggered apoptosis of these cells but not of normal melanocytes. The mammalian transcription factor AP-2 is a sequence-specific DNA-binding protein expressed in neural crest lineages and regulated by retinoic acid. Our preliminary data indicate that both MCAM/MUC18 and c-KIT gene expression is highly regulated by AP-2. In addition, other genes that are involved in the progression of melanoma such as MMP-2, bel-2, E-cadherin, and p21/WAF-1 are also regulated by the transcription factor AP-2. Our laboratory has recently made the observation that while several nonmetastatic melanoma cell lines express AP-2, the highly metastatic cell lines do not express this transcription factor. Therefore, we hypothesize that loss of AP-2 expression may be a crucial event in the development of malignant melanoma. We are therefore proposing the three Specific Aims: 1) to provide a direct evidence for the involvement of AP-2 in the acquisition of the metastatic phenotype by transfecting metastatic cells with w.t. AP-2 and primary melanoma cells with a dominant negative AP-2B genes and subsequently analyze their tumorigenicity and metastatic potential in nude mice. 2) To study the effect of AP-2 and AP-2B on the expression of the above mentioned genes. 3) To evaluate the status of AP-2 expression and function in tumor specimens from patients in well-characterized melanoma database. These experiments will generate valuable information on the progression of melanoma, and help to develop new molecular staging markers and a common target for anti-tumor/metastasis therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA076098-04S1
Application #
6555892
Study Section
Pathology B Study Section (PTHB)
Program Officer
Rosenfeld, Bobby
Project Start
1999-04-01
Project End
2003-08-31
Budget Start
2002-02-01
Budget End
2003-08-31
Support Year
4
Fiscal Year
2002
Total Cost
$43,500
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Shoshan, Einav; Braeuer, Russell R; Kamiya, Takafumi et al. (2016) NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis. Cancer Res 76:3145-55
Braeuer, Russell R; Zigler, Maya; Kamiya, Takafumi et al. (2012) Galectin-3 contributes to melanoma growth and metastasis via regulation of NFAT1 and autotaxin. Cancer Res 72:5757-66
Braeuer, Russell R; Shoshan, Einav; Kamiya, Takafumi et al. (2012) The sweet and bitter sides of galectins in melanoma progression. Pigment Cell Melanoma Res 25:592-601
Zigler, Maya; Villares, Gabriel J; Dobroff, Andrey S et al. (2011) Expression of Id-1 is regulated by MCAM/MUC18: a missing link in melanoma progression. Cancer Res 71:3494-504
Villares, Gabriel J; Zigler, Maya; Dobroff, Andrey S et al. (2011) Protease activated receptor-1 inhibits the Maspin tumor-suppressor gene to determine the melanoma metastatic phenotype. Proc Natl Acad Sci U S A 108:626-31
Zigler, Maya; Kamiya, Takafumi; Brantley, Emily C et al. (2011) PAR-1 and thrombin: the ties that bind the microenvironment to melanoma metastasis. Cancer Res 71:6561-6
Braeuer, Russell R; Zigler, Maya; Villares, Gabriel J et al. (2011) Transcriptional control of melanoma metastasis: the importance of the tumor microenvironment. Semin Cancer Biol 21:83-8
Villares, Gabriel J; Zigler, Maya; Bar-Eli, Menashe (2011) The emerging role of the thrombin receptor (PAR-1) in melanoma metastasis--a possible therapeutic target. Oncotarget 2:8-17
Melnikova, Vladislava O; Dobroff, Andrey S; Zigler, Maya et al. (2010) CREB inhibits AP-2alpha expression to regulate the malignant phenotype of melanoma. PLoS One 5:e12452
Villares, Gabriel J; Dobroff, Andrey S; Wang, Hua et al. (2009) Overexpression of protease-activated receptor-1 contributes to melanoma metastasis via regulation of connexin 43. Cancer Res 69:6730-7

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