PKC in colon cancer cells promotes M1 macrophage polarization via MKK3/6-P38 MAPK pathway
PKC in colon cancer cells promotes M1 macrophage polarization via MKK3/6-P38 MAPK pathway
复制标题
结肠癌细胞中的 PKC 通过 MKK3/6-P38 MAPK 通路促进 M1 巨噬细胞极化
DOI：
10.1002/mc.22822
复制
发表时间：
2018-08-01
影响因子：
4.6
通讯作者：
Gong, Sitang
中科院分区：
文献类型：
--
作者：
Cheng, Yang;Zhu, Yun;Gong, Sitang
肿瘤相关巨噬细胞是结肠癌患者免疫治疗的潜在靶点。PKC在肠道中起肿瘤抑制剂的作用。然而，结肠癌细胞中表达的PKC与肿瘤相关巨噬细胞极化之间的相关性尚未被检测到。在本研究中，PKC的表达和M1巨噬细胞的水平之间的相关性进行了评估在人结肠癌组织。建立不同PKC表达水平的结肠癌细胞移植瘤小鼠模型，研究PKC对M1巨噬细胞极化的影响。结肠癌细胞和分化的巨噬细胞的共培养用于检测体外潜在的相互作用。PKC调节巨噬细胞极化相关的细胞因子的产生，并进一步探讨其机制。我们的研究表明，PKC在人结肠癌组织中的高表达与较好的预后和高M1巨噬细胞含量相关。结肠癌细胞中表达的PKC抑制小鼠结肠癌模型的生长。PKC诱导的巨噬细胞在体外和体内均极化为M1样表型。在机制上，PKC通过MKK 3/6靶向P38以促进IL 12和GM-CSF表达，从而进一步增强M1样巨噬细胞极化。总之，本研究首次提供了结肠癌细胞中PKC通过诱导肿瘤相关巨噬细胞在肿瘤微环境中极化为M1样表型而发挥抗癌作用的证据。PKC通过MKK 3/6-P38信号通路促进IL 12/GM-CSF介导的M1极化。我们的研究表明，调节PKC信号通路可能成为结肠癌治疗的新策略。
Tumor associated macrophages are potential targets of the immune therapy for patients with colon cancer. PKC acts as a tumor suppressor in the intestine. However, the correlation between PKC expressed in colon cancer cells and tumor associated macrophages polarization has never been detected. In the present study, the correlation between PKC expression and level of M1 macrophages was evaluated in human colon cancer tissues. A xenograft mouse model of colon cancer cells with different PKC expression level was constructed to evaluate the effect of PKC on M1 macrophages polarization in vivo. Co-culture of colon cancer cells and differentiated macrophages was used to detect the potential interplay in vitro. PKC regulated production of cytokines which correlated with macrophage polarization and the underlying mechanism was further explored. Our study showed that high PKC expression in human colon cancer tissues correlated with better prognosis and high M1 macrophage content. PKC expressed in colon cancer cells inhibited the growth of colon cancer in mice model. PKC induced macrophages polarized to the M1-like phenotype both in vitro and in vivo. Mechanistically, PKC targeted P38 via MKK3/6 to promote IL12 and GM-CSF expression which further enhanced M1-like macrophages polarization. In conclusion, this study provided evidence for the first time that PKC in colon cancer cells play an anticancer action by inducing the polarization of tumor associated macrophages to M1-like phenotype in the tumor microenvironment. PKC promoted IL12/GM-CSF-mediated M1 polarization through MKK3/6-P38 signaling pathway. Our investigation suggested that modulation of the PKC signaling pathway might serve as a novel strategy for colon cancer therapy.