High-mobility group box-1 contributes tumor angiogenesis under interleukin-8 mediation during gastric cancer progression.
High-mobility group box-1 contributes tumor angiogenesis under interleukin-8 mediation during gastric cancer progression.
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DOI：
10.1111/cas.13288
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发表时间：
2017-08
期刊：
影响因子：
5.7
通讯作者：
Lim JB
中科院分区：
文献类型：
--
作者：
Chung HW;Lim JB
许多可溶性因子参与肿瘤血管生成。因此，筛选新的可溶性因子来有效控制胃癌（GC）中的肿瘤血管生成是有价值的。我们研究了细胞外高迁移率族蛋白B1（HMGB 1）及其相关可溶性因子在胃癌肿瘤血管生成中的作用。在临床上，我们使用GC血清样本（n = 120）测量HMGB 1和GC相关细胞因子/趋化因子的血清水平，并使用人GC组织（n = 27）通过CD 34免疫染色计算微血管密度（MVD）。采用直线回归分析血清HMGB 1水平与MVD、细胞因子/趋化因子水平的相关性。作为HMGB 1的体外血管生成测定，使用不同组织学类型的人GC细胞（N87和KATOIII）进行HUVEC迁移和毛细管形成测定。CD 34阳性微血管在胃癌早期即有表达，但MVD随胃癌分期的增加而增加，且与血清HMGB 1水平密切相关（R = 0.608，P = 0.01）。在rhHMGB 1处理的或HMGB 1 ‐TF GC细胞的条件培养基中培养的HUVEC显示出显著增强的迁移和管形成活性。在N87和KATOIII细胞中，这些作用被抗HMGB 1抗体或HMGB 1 siRNA消除（均P < 0.05）。在测试的细胞因子/趋化因子中，白细胞介素-8（IL-8）是与血清HMGB 1相关性最显著的细胞因子（P < 0.001），并且rhHMGB 1或HMGB 1-TF增强的HUVEC迁移和管形成活性被IL-8抑制显著逆转。这些结果表明，过表达的HMGB 1通过IL-8介导促进肿瘤血管生成，HMGB 1和IL-8的联合靶向可以控制GC中的肿瘤血管生成。
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 the tumor angiogenesis of 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 CD34 immunostaining 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, HUVEC migration and capillary tube formation assay were carried out using different histological types of human GC cells (N87 and KATOIII). CD34‐positive microvessels were detected from early GC, but MVD increased according to GC stages, and were closely correlated with serum HMGB1 levels (R = 0.608, P = 0.01). The HUVECs cultured in conditioned media 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, interleukin‐8 (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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