Anoxia-Induced Up-Regulation of Interleukin-8 in Human Malignant Melanoma : A Potential Mechanism for High Tumor Aggressiveness

• Published in: The American journal of pathology Vol. 155; no. 3; pp. 753 - 763
• Main Authors: Kunz, Manfred, Hartmann, Anke, Flory, Egbert, Toksoy, Atiye, Koczan, Dirk, Thiesen, Hans-Jurgen, Mukaida, Nafoumi, Neumann, Manfred, Rapp, Ulf Rudiger, Brocker, Eva-Bettina, Gillitzer, Reinhard
• Format: Journal Article
• Language: English
• Published: Bethesda, MD ASIP 01.09.1999; American Society for Investigative Pathology
• Subjects: Antigens, CD - metabolism; Biological and medical sciences; Cell Hypoxia - physiology; Dermatology; Gene Expression; Genes, Reporter; Humans; Immunohistochemistry; In Situ Hybridization; Interleukin-8 - metabolism; Medical sciences; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Necrosis; Neoplasm Invasiveness; Neoplasm Metastasis; NF-kappa B - metabolism; Promoter Regions, Genetic; Receptors, Chemokine - metabolism; Receptors, Interleukin - metabolism; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Regular; RNA, Messenger - biosynthesis; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Transcription Factor AP-1 - metabolism; Transcriptional Activation - genetics; Transcriptional Activation - physiology; Tumor Cells, Cultured; Tumors of the skin and soft tissue. Premalignant lesions; Up-Regulation; Human; Immunohistochemistry; Skin disease; Anoxia; Cytokine; Malignant tumor; Metastasis; Necrosis; Pathology; Regulation(control); Malignant melanoma; Tumor progression; Skin; Molecular biology; Interleukin 8; Aggressiveness
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)65174-7

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-kappaB-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-kappaB 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.