High mobility group box‐1‐inducible melanoma inhibitory activity is associated with nodal metastasis and lymphangiogenesis in oral squamous cell carcinoma

Abstract

Melanoma inhibitory activity (MIA) is an 11-kDa secretory protein isolated from malignant melanoma cells that is correlated with invasion and metastasis in various human malignancies. We examined MIA expression in 62 oral squamous cell carcinomas (OSCC) by immunohistochemistry. MIA expression was significantly associated with nodal metastasis (P = 0.00018). MIA expression was also associated with expression of high mobility group box-1 (HMGB1) (P < 0.0001) and lymph vessel density (P < 0.0001). Expression levels of MIA, HMGB1, nuclear factor kB (NFkB) p65 and HMGB1-NFkB p65 binding were significantly higher in a metastatic human OSCC cell line (HSC3) than those in a non-metastatic OSCC cell line (HSC4). H ead and neck cancer is the sixth most common malignancy worldwide and the first leading cause of cancer death in South Asia.(1) About 300 000 patients develop OSCC every year in the world.(2,3) OSCC has a high potential for nodal metastasis and locoregional invasion, (4) from which over 50% of patients die.(5,6) To control lymph-node metastasis of OSCC, we need to study the molecular aspects of the mechanism of metastasis.MIA is an 11-kDa secretory protein isolated from supernatants of HTZ-19 malignant melanoma cells, (7,8) the gene locus of which is mapped to chromosome 19q13.32-13.33.(9) Although previous reports indicated that MIA is correlated with invasion and metastasis in malignant melanoma, (10)(11)(12) breast cancer,chondrosarcoma, (13) glioma, (14) and pancreatic cancer,the definite functions of MIA for cancer cells are still unclear.HMGB1 has a dual role as an extracellular secretory protein and a chromosomal structural protein.(16) HMGB1 works as a cytokine or a growth factor in neural ontogenesis, septic inflammation and neoplasm. HMGB1 is also considered an amphoterin, which is isolated as a motility factor in neurite outgrowth.(17) We previously reported coexpression of HMGB1 and receptor for advanced glycation end products (RAGE), which is a major membrane receptor for HMGB1 and is significantly associated with tumor progression and metastasis (18)(19)(20)(21)(22)(23)(24) and suppression of tumor-associated macrophages. (25,26) As a chromatin structural protein, HMGB1 participates in gene expression, DNA repair and functions of the p53 family.(27) Recently, HMGB1 was revealed to interact with NFkB p65 to accelerate MIA expression. (28,29) HMGB1 and NFkB p65 concurrently bind to a 30-bp region in the promoter region of the MIA gene designated as the highly conserved region (HCR).MIA is suspected to play an important role as a pro-metastatic factor in HMGB1-overexpressing cancers. In the present study, we analyzed the relationship between MIA expression and nodal metastasis and HMGB1 expression in human OSCC. Materials and MethodsTumor specimens. Sixty-two formalin-fixed, paraffin-embedded specimens of primary OSCC were randomly selected at Nara Medical University Hospital, Kashihara, Japan. None of the samples was treated using neo-adjuvant therapy. Medical records and prognostic follow-up data w...

HMGB1 was a pivotal synergistic effecor for CpG oligonucleotide to enhance the progression of human lung cancer cells

“…[8][9][10] Recently, accumulating data suggested that HMGB1 expression was correlated with tumor development. [10][11][12][13] Upregulated expression of HMGB1 has been found in many tumor types including lung cancer. 3 However, high-mobility group box 1 (hMGB1) has been implicated in a variety of biologically important processes, including transcription, DNa repair, differentiation, development and extracellular signaling.…”

Immunogene Zelltodmarker HMGB1 und sRAGE als neue prädiktive und prognostische Serum Biomarker bei Tumorerkrankungen/Immunogenic cell death markers HMGB1 and sRAGE as new predictive and prognostic serum biomarkers in cancer disease

“…Da HMGB1 auch die Neubildung von Lymphgef ä ß en f ö rdert, k ö nnte es auch zur lymphogenen Metastasierung beitragen. So wurde beim oralen Plattenepithelkarzinom eine Korrelation der HMGB1-Werte mit der Dichte der Lymphgef ä ß e und dem Lymphknoten-Status festgestellt [108] .…”

Low-Anticoagulant Heparins in the Treatment of Metastasis

“…Taguchi et al found that blockade of HMGB-RAGE signaling suppressed tumor growth as a result of decreased cell migration and invasiveness rather than proliferation or apoptosis (Taguchi et al, 2000). HMGB1 alone or by interaction with NF-kBp65 has been shown to bind specific region of melanocyte inhibitory activity (MIA) promoter in melanocytes and increase the expression of MIA protein, which enhances migration and invasion of tumor cells (Poser et al, 2003;Sasahira et al, 2008). HMGB1 was isolated using heparin-sepharose chromatography (Rauvala & Pihlaskari, 1987) and later was identified to contain a heparin-binding sequence in its amino terminus, suggesting its affinity for heparin (Cardin & Weintraub, 1989).…”