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


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).


CONCLUSIONS
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.
Karjalainen
J M
JM
Department of Surgery, Kuopio University Hospital, Finland. jari.karjalainen@uku.fi
Kellokoski
J K
JK
Eskelinen
M J
MJ
Alhava
E M
EM
Kosma
V M
VM
D000328:Adult; D000368:Aged; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000401:mortality*; D008875:Middle Aged; D012878:Skin Neoplasms / Q000401:mortality*; D016019:Survival Analysis; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050656:Transcription Factor AP-2; D014157:Transcription Factors