High-mobility group box-1 contributes tumor angiogenesis under interleukin-8 mediation during gastric cancer progression

Abstract

Many soluble factors are involved in tumor angiogenesis. Thus, it is valuable to identify novel soluble factors for effective control of tumor angiogenesis in gastric cancer (GC). We investigated the role of extracellular high-mobility group box-1 (HMGB1) and its associated soluble factors in tumor angiogenesis of gastric cancer (GC). Clinically, we measured serum levels of HMGB1 and GC-associated cytokines/chemokines using GC serum samples (n=120), and calculated microvessel density (MVD) by performing CD34 immuno-staining using human GC tissues (n=27). Then, we analyzed the correlation of serum HMGB1 levels with MVD or that with cytokine/chemokine levels by linear regression. As in vitro angiogenesis assay for HMGB1, human umbilical vein endothelial cell (HUVEC) migration and capillary tube formation assay were conducted using different histological types of human GC cells (N87, KATOIII). Resultingly, CD34-positive microvessels were detected from early GC (EGC), but MVD increased according to GC stages, and were closely correlated with serum HMGB1 levels (R=0.608, P=0.01). HUVECs cultured in conditioned media (CM) derived from rhHMGB1-treated or HMGB1-TF GC cells showed remarkably enhanced migration and tube formation activities. These effects were abrogated by anti-HMGB1 antibody or HMGB1 siRNA in both N87 and KATOIII cells (all P<0.05). Among tested cytokines/chemokines, IL-8 was the most remarkable cytokine correlated with serum HMGB1 (P<0.001), and enhanced HUVEC migration and tube formation activities by rhHMGB1 or HMGB1-TF were significantly reversed by IL-8 inhibition. These results indicate overexpressed HMGB1 contributes to tumor angiogenesis through IL-8 mediation, and combined targeting of HMGB1 and IL-8 can control tumor angiogenesis in GC.

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