Department of Digestive, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
Mol Carcinog. 2018 Aug;57(8):1017-1029. doi: 10.1002/mc.22822. Epub 2018 May 2.
Tumor associated macrophages are potential targets of the immune therapy for patients with colon cancer. PKCα acts as a tumor suppressor in the intestine. However, the correlation between PKCα expressed in colon cancer cells and tumor associated macrophages polarization has never been detected. In the present study, the correlation between PKCα expression and level of M1 macrophages was evaluated in human colon cancer tissues. A xenograft mouse model of colon cancer cells with different PKCα expression level was constructed to evaluate the effect of PKCα on M1 macrophages polarization in vivo. Co-culture of colon cancer cells and differentiated macrophages was used to detect the potential interplay in vitro. PKCα regulated production of cytokines which correlated with macrophage polarization and the underlying mechanism was further explored. Our study showed that high PKCα expression in human colon cancer tissues correlated with better prognosis and high M1 macrophage content. PKCα expressed in colon cancer cells inhibited the growth of colon cancer in mice model. PKCα induced macrophages polarized to the M1-like phenotype both in vitro and in vivo. Mechanistically, PKCα 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 PKCα in colon cancer cells play an anticancer action by inducing the polarization of tumor associated macrophages to M1-like phenotype in the tumor microenvironment. PKCα promoted IL12/GM-CSF-mediated M1 polarization through MKK3/6-P38 signaling pathway. Our investigation suggested that modulation of the PKCα signaling pathway might serve as a novel strategy for colon cancer therapy.
肿瘤相关巨噬细胞是结肠癌患者免疫治疗的潜在靶点。PKCα 在肠道中作为一种肿瘤抑制因子发挥作用。然而，结肠癌细胞中表达的 PKCα 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，评估了人结肠癌组织中 PKCα 表达与 M1 巨噬细胞水平之间的相关性。构建了 PKCα 表达水平不同的结肠癌细胞的异种移植小鼠模型，以评估 PKCα 对体内 M1 巨噬细胞极化的影响。体外共培养结肠癌细胞和分化的巨噬细胞，以检测潜在的相互作用。PKCα 调节细胞因子的产生，这与巨噬细胞极化相关，并且进一步探讨了潜在的机制。我们的研究表明，人结肠癌组织中高 PKCα 表达与较好的预后和高水平的 M1 巨噬细胞含量相关。在小鼠模型中，结肠癌细胞中表达的 PKCα 抑制结肠癌的生长。PKCα 在体外和体内均诱导巨噬细胞向 M1 样表型极化。在机制上，PKCα 通过 MKK3/6 靶向 P38 以促进 IL12 和 GM-CSF 的表达，从而进一步增强 M1 样巨噬细胞的极化。总之，这项研究首次提供了证据，表明结肠癌细胞中的 PKCα 通过诱导肿瘤相关巨噬细胞向肿瘤微环境中的 M1 样表型极化来发挥抗癌作用。PKCα 通过 MKK3/6-P38 信号通路促进 IL12/GM-CSF 介导的 M1 极化。我们的研究表明，调节 PKCα 信号通路可能成为结肠癌治疗的一种新策略。
