Journal of Clinical Oncology, Vol 16, 3584-3591, Copyright © 1998 by American Society of Clinical Oncology

ARTICLES

Downregulation of transcription factor AP-2 predicts poor survival in stage I cutaneous malignant melanoma

JM Karjalainen, JK Kellokoski, MJ Eskelinen, EM Alhava and VM Kosma
Department of Surgery, Kuopio University Hospital, Finland. jari.karjalainen@uku.fi

PURPOSE: The transcription factor, activator protein (AP)-2, a 52-kd DNA-binding protein, is suggested to inhibit tumor growth through the activation of p21. To test this hypothesis, we analyzed AP-2 and p21 protein expressions in stage I cutaneous malignant melanomas to clarify their significance with regard to tumor progression and survival. PATIENTS AND METHODS: A consecutive series of 369 clinical stage I cutaneous malignant melanoma patients were investigated using immunohistochemistry. The detected expression levels were correlated with each other, with clinicopathologic data, and with melanoma survival. RESULTS: The loss of AP-2 expression was significantly associated with low p21 expression (P=.007), high tumor thickness (P=.001), high Clark's level (P=.046), high tumor-node-metastasis (TNM) category (P=.006), recurrent disease (P=.001), and male sex (P=.03). Tumor thickness, Clark's level, TNM category, bleeding, AP-2 index, and sex were all important predictors of both recurrence-free survival (RFS) and overall survival (OS) of melanoma in this order. In Cox's multivariate analysis, high tumor thickness (P=.0001), low AP-2 index (P=.0153), and bleeding (P=.0143) predicted poor RFS. Poor OS was predicted by high tumor thickness (P=.0008) and bleeding (P=.0092). CONCLUSION: The loss of AP-2 expression seems to be associated with malignant transformation and tumor progression in cutaneous malignant melanoma. This tumor-suppressive action of AP-2 may be mediated through p21 regulation. Furthermore, decreased AP-2 expression is independently associated with elevated risk of subsequent metastatic behavior of stage I cutaneous malignant melanoma.

This article has been cited by other articles:

				F. Orso, E. Penna, D. Cimino, E. Astanina, F. Maione, D. Valdembri, E. Giraudo, G. Serini, P. Sismondi, M. De Bortoli, et al. AP-2{alpha} and AP-2{gamma} regulate tumor progression via specific genetic programs FASEB J, August 1, 2008; 22(8): 2702 - 2714. [Abstract] [Full Text] [PDF]

				W.-G. Deng, G. Jayachandran, G. Wu, K. Xu, J. A. Roth, and L. Ji Tumor-specific Activation of Human Telomerase Reverses Transcriptase Promoter Activity by Activating Enhancer-binding Protein-2beta in Human Lung Cancer Cells J. Biol. Chem., September 7, 2007; 282(36): 26460 - 26470. [Abstract] [Full Text] [PDF]

				N. Wajapeyee, R. Britto, H. M. Ravishankar, and K. Somasundaram Apoptosis Induction by Activator Protein 2{alpha} Involves Transcriptional Repression of Bcl-2 J. Biol. Chem., June 16, 2006; 281(24): 16207 - 16219. [Abstract] [Full Text] [PDF]

				A. J. Berger, D. W. Davis, C. Tellez, V. G. Prieto, J. E. Gershenwald, M. M. Johnson, D. L. Rimm, and M. Bar-Eli Automated Quantitative Analysis of Activator Protein-2{alpha} Subcellular Expression in Melanoma Tissue Microarrays Correlates with Survival Prediction Cancer Res., December 1, 2005; 65(23): 11185 - 11192. [Abstract] [Full Text] [PDF]

				T. Rothhammer, I. Poser, F. Soncin, F. Bataille, M. Moser, and A.-K. Bosserhoff Bone Morphogenic Proteins Are Overexpressed in Malignant Melanoma and Promote Cell Invasion and Migration Cancer Res., January 15, 2005; 65(2): 448 - 456. [Abstract] [Full Text] [PDF]

				Q. Li and R. H. Dashwood Activator Protein 2{alpha} Associates with Adenomatous Polyposis Coli/{beta}-Catenin and Inhibits {beta}-Catenin/T-cell Factor Transcriptional Activity in Colorectal Cancer Cells J. Biol. Chem., October 29, 2004; 279(44): 45669 - 45675. [Abstract] [Full Text] [PDF]

				D. B. Douglas, Y. Akiyama, H. Carraway, S. A. Belinsky, M. Esteller, E. Gabrielson, S. Weitzman, T. Williams, J. G. Herman, and S. B. Baylin Hypermethylation of a Small CpGuanine-Rich Region Correlates with Loss of Activator Protein-2{alpha} Expression during Progression of Breast Cancer Cancer Res., March 1, 2004; 64(5): 1611 - 1620. [Abstract] [Full Text] [PDF]

				M. Ruiz, C. Pettaway, R. Song, O. Stoeltzing, L. Ellis, and M. Bar-Eli Activator Protein 2{alpha} Inhibits Tumorigenicity and Represses Vascular Endothelial Growth Factor Transcription in Prostate Cancer Cells Cancer Res., January 15, 2004; 64(2): 631 - 638. [Abstract] [Full Text] [PDF]

				N. Wajapeyee and K. Somasundaram Cell Cycle Arrest and Apoptosis Induction by Activator Protein 2{alpha} (AP-2{alpha}) and the Role of p53 and p21WAF1/CIP1 in AP-2{alpha}-mediated Growth Inhibition J. Biol. Chem., December 26, 2003; 278(52): 52093 - 52101. [Abstract] [Full Text] [PDF]

				C. Tellez, M. McCarty, M. Ruiz, and M. Bar-Eli Loss of Activator Protein-2{alpha} Results in Overexpression of Protease-activated Receptor-1 and Correlates with the Malignant Phenotype of Human Melanoma J. Biol. Chem., November 21, 2003; 278(47): 46632 - 46642. [Abstract] [Full Text] [PDF]

				M.-F. Demierre and L. Nathanson Chemoprevention of Melanoma: An Unexplored Strategy J. Clin. Oncol., January 1, 2003; 21(1): 158 - 165. [Abstract] [Full Text] [PDF]

				L. A. McPherson, A. V. Loktev, and R. J. Weigel Tumor Suppressor Activity of AP2alpha Mediated through a Direct Interaction with p53 J. Biol. Chem., November 15, 2002; 277(47): 45028 - 45033. [Abstract] [Full Text] [PDF]

				J. Pellikainen, V. Kataja, K. Ropponen, J. Kellokoski, T. Pietilainen, J. Bohm, M. Eskelinen, and V.-M. Kosma Reduced Nuclear Expression of Transcription Factor AP-2 Associates with Aggressive Breast Cancer Clin. Cancer Res., November 1, 2002; 8(11): 3487 - 3495. [Abstract] [Full Text] [PDF]

				M. Ruiz, P. Troncoso, C. Bruns, and M. Bar-Eli Activator Protein 2{alpha} Transcription Factor Expression Is Associated with Luminal Differentiation and Is Lost in Prostate Cancer Clin. Cancer Res., December 1, 2001; 7(12): 4086 - 4095. [Abstract] [Full Text] [PDF]

				O. Nyormoi, Z. Wang, D. Doan, M. Ruiz, D. McConkey, and M. Bar-Eli Transcription Factor AP-2{alpha} Is Preferentially Cleaved by Caspase 6 and Degraded by Proteasome during Tumor Necrosis Factor Alpha-Induced Apoptosis in Breast Cancer Cells Mol. Cell. Biol., August 1, 2001; 21(15): 4856 - 4867. [Abstract] [Full Text] [PDF]

				J. M. Karjalainen, R. H. Tammi, M. I. Tammi, M. J. Eskelinen, U. M. Agren, J. J. Parkkinen, E. M. Alhava, and V.-M. Kosma Reduced Level of CD44 and Hyaluronan Associated with Unfavorable Prognosis in Clinical Stage I Cutaneous Melanoma Am. J. Pathol., September 1, 2000; 157(3): 957 - 965. [Abstract] [Full Text] [PDF]

				S. Wankhade, Y. Yu, J. Weinberg, M. A. Tainsky, and P. Kannan Characterization of the Activation Domains of AP-2 Family Transcription Factors J. Biol. Chem., September 15, 2000; 275(38): 29701 - 29708. [Abstract] [Full Text] [PDF]

				I. Poser, D. Dominguez, A. G. de Herreros, A. Varnai, R. Buettner, and A. K Bosserhoff Loss of E-cadherin Expression in Melanoma Cells Involves Up-regulation of the Transcriptional Repressor Snail J. Biol. Chem., June 29, 2001; 276(27): 24661 - 24666. [Abstract] [Full Text] [PDF]