SFRP5-Wnt5a调控胃黏膜巨噬细胞募集和活化的研究

Excessive recruitment and M2 activation of macrophage in gastric mucosa plays important roles in the transforming process from chronic gastric inflammation to precancerous lesions and gastric cancer, however, the underlying mechanisms about abnormal macrophage recruitment and activation are not completely understood, and few studies focus on them. Secreted Frizzled-Related Protein 5 (SFRP5) was found to be only expressed in several tissues, such as fat and gastric mucosa, but its biological roles in gastric mucosa remain unknown. Some recent studies have shown that Helicobacter pylori can induce gastric epithelial cells to express Wnt5a which can upregulate COX-2 expression; and PGE2，a product of COX-2, can induce macrophage recruitment and M2 activation; in addition, SFRP5 is able to suppress Wnt5a signal pathway. Taken together, these results indicae that SFRP5-Wnt5a may be involved in abnormal macrophage recruitment and activation in gastric mucosa. In the present study, we intend to set up SFRP5 knockdown and Wnt5a overexpression cells, to explore the effects of SFRP5-Wnt5a on macrophage chemoattraction and activation in vitro and reveal the underlying molecular mechanisms, then to find the target for blocking the transforming process from chronic gastric inflammation to precancerous lesions and gastric cancer.

巨噬细胞过度募集和M2活化是胃黏膜慢性炎症转向癌前病变及胃癌的重要原因之一，然而关于胃黏膜中巨噬细胞募集和活化的调控机制目前尚缺乏研究。分泌型Frizzled相关蛋白5（SFRP5）仅在脂肪、胃黏膜等少数组织中存在表达，但其在胃黏膜中的生物学意义仍不清楚。近期一系列研究显示：幽门螺杆菌可诱导胃上皮细胞表达Wnt5a；Wnt5a能上调环氧化酶2（COX-2）表达，其产物前列腺素E2（PGE2）可促进巨噬细胞募集和M2活化；而SFRP5则阻抑Wnt5a信号通路活性，这些结果初步表明SFRP5和Wnt5a可能共同参与了胃黏膜巨噬细胞异常募集和活化过程。本研究拟建立SFRP5基因敲除且Wnt5a高表达细胞系，体外探索SFRP5-Wnt5a对巨噬细胞趋化和活化的调控作用及相关分子生物学机制，为临床上阻断胃黏膜慢性炎症向癌前病变及胃癌演变提供干预靶点。

巨噬细胞过度募集和活化是胃黏膜慢性炎症转向癌前病变及胃癌的重要原因之一，然而关于胃黏膜中巨噬细胞募集和活化的调控机制目前尚缺乏研究。申请者前期研究显示胃癌组织中Wnt蛋白家族成员Wnt5a表达增多，而Wnt5a拮抗因子分泌型Frizzled相关蛋白5（SFRP5）表达缺失；同时近期一些研究显示Wnt5a与SFRP5分别是促炎因子及抗炎因子，故本研究欲探讨SFRP5-Wnt5a系统表达失衡是否影响巨噬细胞的募集和活化。研究结果显示：Wnt5a可诱导胃上皮细胞及巨噬细胞表达巨噬细胞趋化蛋白1（MCP-1，又名CCL2），并促进巨噬细胞的趋化运动和细胞骨架收缩；Wnt5a可刺激巨噬细胞分泌炎性细胞因子。IL-1β、NFκB、JNK等信号分子介导了Wnt5a对巨噬细胞趋化及活化的诱导作用。胃上皮细胞SFRP5可阻断Wnt5a对巨噬细胞趋化和活化的诱导作用。综上所述，这些研究显示Wnt5a过度产生及SFRP5表达缺失共同引起了巨噬细胞过度的募集和活化。本项目首次揭示了Wnt5a-SFRP5系统对巨噬细胞趋化和活化的调控机制，并提示Wnt5a-SFRP5系统失衡可能引起胃黏膜内巨噬细胞过度募集和活化，进而导致胃黏膜内慢性炎症及肿瘤的发生。同时本项目对相关信号通路的研究，为防止胃黏膜内巨噬细胞过度募集和活化，及慢性炎症、肿瘤的发生，提供新的靶点及依据。

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