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Failure in post-transcriptional processing is a possible inactivation mechanism of AP-2alpha in cutaneous melanoma
J M Karjalainen1, J K Kellokoski, A J Mannermaa
1Department of Surgery, University of Kuopio and Kuopio University Hospital, Finland.
Abstract:
The loss of transcription factor AP-2alpha expression has been shown to associate with tumourigenicity of melanoma cell lines and poor prognosis in primary cutaneous melanoma. Altogether these findings suggest that the gene encoding AP-2alpha (TFAP2A) acts as a tumour suppressor in melanoma. To learn more of AP-2alpha's down-regulation mechanisms, we compared the immunohistochemical AP-2alpha protein expression patterns with the corresponding mRNA expression detected by in situ hybridization in 52 primary melanomas. Of the 25 samples with AP-2alpha protein negative areas, 16 (64%) expressed mRNA throughout the consecutive section. Nine specimens (36%) contained equally mRNA- and protein-negative areas, suggesting that the loss of AP-2alpha protein associated with lack of the mRNA transcript. The highly AP-2alpha protein-positive tumours (n = 27) were concordantly mRNA positive in 25 (92.6%) cases. Thirteen primary tumours were further analysed using microsatellite markers D6S470 and D6S263 for loss of heterozygosity (LOH) of a locus harbouring TFAP2A. LOHs or chromosome 6 monosomy were found in four out of five (80%) informative AP-2alpha mRNA- and protein-negative tumour areas, but also within five out of 13 (38%) informative AP-2alpha mRNA-positive tumour areas. This chromosome region is thus suggestive of harbouring a putative tumour suppressor gene of cutaneous melanoma, but this referring specifically to TFAP2A could not be completely verified in this analysis. We conclude that a failure in post-transcriptional processing of AP-2alpha is a possible inactivation mechanism of AP-2alpha in cutaneous melanoma.
Insights
Loss of AP-2alpha (TFAP2A) expression correlates with melanoma progression. Post-transcriptional regulation, not just gene mutation, may explain its reduced levels in melanoma, suggesting TFAP2A acts as a tumor suppressor.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Loss of transcription factor AP-2alpha (TFAP2A) expression is linked to melanoma tumor growth and poor patient prognosis.
- These observations suggest TFAP2A functions as a tumor suppressor gene in melanoma development.
Purpose of the Study:
- To investigate the mechanisms underlying AP-2alpha down-regulation in melanoma.
- To correlate AP-2alpha protein expression with its mRNA levels and assess potential genetic alterations in primary cutaneous melanoma.
Main Methods:
- Immunohistochemistry was used to assess AP-2alpha protein expression in 52 primary melanomas.
- In situ hybridization was employed to detect corresponding mRNA expression.
- Microsatellite markers (D6S470, D6S263) were used to analyze loss of heterozygosity (LOH) at the TFAP2A locus.
Main Results:
- A significant portion of tumors (36%) showed concordant loss of both AP-2alpha protein and mRNA, indicating transcriptional down-regulation.
- However, 64% of protein-negative areas still expressed mRNA, suggesting post-transcriptional mechanisms are involved.
- Loss of heterozygosity or monosomy at the chromosome 6 locus was observed in both mRNA/protein-negative and mRNA-positive tumor areas, implicating this region in melanoma but not definitively confirming TFAP2A as the sole driver.
Conclusions:
- Post-transcriptional dysregulation is a likely mechanism for AP-2alpha inactivation in cutaneous melanoma.
- While TFAP2A is implicated as a tumor suppressor, its precise role and the contribution of genetic alterations require further investigation.