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From the Department of Dermatology,*
Institut für
Medizinische Strahlenkunde und
Zellforschung,¶
Institute of
Pathology/ Department of Molecular
Pathology,§
Institute of
Immunology,||
University of Würzburg,
Würzburg, Germany; the Department of Molecular
Pharmacology,
Kanazawa University, Kanazawa,
Japan; and the Department of Immunology,
University of Rostock, Rostock, Germany
Besides its proinflammatory properties, interleukin-8
(IL-8) has been suggested as an important promoter for melanoma growth.
To study the role of IL-8 in melanoma biology, we determined
the in vivo expression of IL-8 mRNA by in
situ hybridization in primary melanoma lesions and metastases.
High levels of melanoma cell-associated IL-8-specific transcripts were
exclusively detected in close vicinity of necrotic/hypoxic areas of
melanoma metastases, whereas both in primary melanomas and in
non-necrotic metastases IL-8 expression was low or absent. To analyze
further the up-regulation of IL-8 mRNA expression in necrotic/hypoxic
tumor areas, human melanoma cell lines of different
aggressiveness exposed to severe hypoxic stress (anoxia) were used as
an in vitro model. Anoxia induced IL-8 mRNA and protein
expression in the highly aggressive/metastatic cell lines MV3 and BLM
but not in the low aggressive cell lines IF6 and 530. As shown by IL-8
promoter-dependent reporter gene analysis and mRNA stability
assays, elevated mRNA levels in melanoma cells were due to both
enhanced transcriptional activation and enhanced IL-8 mRNA stability.
Interestingly, transcriptional activation was abolished by
mutations in the AP-1 and the NF-
B-like binding motifs,
indicating that both sites are critical for IL-8 induction.
Concomitantly, anoxia induced an enhanced binding activity of
AP-1 and NF-B transcription factors only in the highly aggressive
cells. From our in vitro and in vivo data
we suggest that anoxia-induced regulation of IL-8 might be a
characteristic feature of aggressive tumor cells, thus
indicating that IL-8 might play a critical role for tumor progression
in human malignant melanoma.
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