摘要目的 探讨白细胞介素-1受体拮抗剂(interleukin-1 receptor antagonist,IL-1 ra)和肝细胞生长因子(hepatocyte growth factor,HGF)在结肠癌转移过程中的作用机制,并探讨癌细胞-基质细胞在微环境中的相互作用关系.方法 用RT-PCR及Western blot检测IL-1α、HGF和其受体c-Met在结肠癌细胞株和基质细胞中的表达,ELISA实验检测IL-1α、HGF及IL-1 ra之间的生物学关系.构建癌细胞-基质细胞共同培养系统,用细胞增殖、侵袭及新生血管实验检测HGF对结肠癌转移能力的影响,同时检测IL-1ra的作用.结果 IL-1α表达水平与结肠癌细胞株的肝转移能力密切相关.IL-1α能够提高成纤维细胞HGF的分泌水平(P＜0.01),而IL-1ra能抑制IL-1α的提高作用(P＜0.01).HGF通过促进血管内皮细胞的增生、迁移而增强肿瘤的新生血管形成(P＜0.01),IL-1 ra能够抑制肿瘤的新生血管形成(P＜0.01).结论 自分泌的IL-1α和旁分泌的HGF相互作用共同调控结肠癌的转移;而IL-1 ra通过阻断IL-1α和HGF信号途径抑制结肠癌的转移.

abstractsObjective The aim of this study was to investigate the co-operative role of HGF and IL-1ra in metastatic processes by interactions between colon cancer cells and stromal cells in their microenvironment.Methods Expression of IL-1α,HGF and c-Met mRNA and proteins were determined by RT-PCR and Western blot.The effect of HGF on metastatic potential was evaluated by proliferation,invasion,and angiogenesis assays using an in vitro system consisting of co-cultured tumor cells and stromal cells.Results IL-1α expression was closely correlated with metastatic potential,and cancer cell-derived IL-1α significantly promoted HGF expression by fibroblasts (P ＜ 0.01).HGF enhanced the migration and proliferation of human umbilical vein endothelial cells (HUVECs),and angiogenesis (P ＜ 0.01).The high liver-metastatic colon cancer cell line (HT-29),which secretes IL-1 α,significantly enhanced angiogenesis compared to the low liver-metastatic cell line (CaCo-2),which does not produce IL-1 α (P ＜ 0.01).IL-1 ra significantly inhibit migration,proliferation and angiogenesis (P ＜ 0.01).Conclusions Autocrine IL-1α and paracrine HGF enhance the metastatic potential of colon cancer cells;IL-1ra inhibit the metastatic potential of colon cancer cells by blocking IL-1α and HGF signaling pathways.