The Agpat4/LPA axis in colorectal cancer cells regulates antitumor responses via p38/p65 signaling in macrophages.
The Agpat4/LPA axis in colorectal cancer cells regulates antitumor responses via p38/p65 signaling in macrophages.
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结直肠癌细胞中的 Agpat4/LPA 轴通过巨噬细胞中的 p38/p65 信号传导调节抗肿瘤反应。
DOI：
10.1038/s41392-020-0117-y
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Miao Hongming
中科院分区：
文献类型：
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作者：
Zhang Dapeng;Shi Rongchen;Xiang Wei;Kang Xia;Tang Bo;Li Chuan;Gao Linfeng;Zhang Xuan;Zhang Lili;Dai Rongyang;Miao Hongming
脂代谢重编程在调节结直肠癌(CRC)的进展中起着重要作用。然而，溶血磷脂酸(LPA)代谢对结直肠癌发生的影响尚不完全清楚。在这里，我们比较了人类结直肠癌组织和癌旁组织的mRNA水平，并集中在显著丰富的LPA代谢途径上。我们鉴定和验证了1-酰基甘油-3-磷酸-O-酰基转移酶4(Agpat4)在结直肠癌组织中异常表达，并预测结直肠癌患者的预后不良。在结直肠癌细胞中操纵Agpat4的表达对结直肠癌细胞的生长和迁移没有影响，而在皮下和腹膜移植模型中，Agpat4的沉默抑制了结直肠癌细胞的生长。在机制上，Agpat4沉默通过LPA受体1和3诱导结直肠癌细胞释放LPA，并使巨噬细胞极化为M1样表型。这种M1激活的特点是p38/p65信号增强和促炎细胞因子增加，促进了肿瘤微环境中CD4+和CD8+T细胞的渗透和激活。Agpat4/LPA/p38/p65轴调控巨噬细胞极化、T细胞活性和结直肠癌进展。值得注意的是，LPA和常规化疗药物的联合治疗协同抑制了CRC的发展。综上所述，我们的结果表明，结直肠癌细胞中的Agpat4/LPA轴调控p38/p65信号依赖的巨噬细胞极化、T细胞激活和结直肠癌进展。Agpat4/LPA/p38/p65轴可能是临床治疗的潜在靶点。
Lipid metabolic reprogramming plays an essential role in regulating the progression of colorectal cancer (CRC). However, the effect of lysophosphatidic acid (LPA) metabolism on CRC development is incompletely characterized. Here, we compared the mRNA levels of human CRC tissues to those of paracarcinoma tissues and focused on the notably enriched LPA metabolic pathways. We identified and verified that 1-acylglycerol-3-phosphate O-acyltransferase 4 (Agpat4) was aberrantly expressed in CRC tissues and predicted poor survival in CRC patients. Manipulating Agpat4 expression in CRC cells did not affect the growth or migration of CRC cells in vitro, whereas Agpat4 silencing suppressed CRC cell growth in subcutaneous and peritoneal xenograft models. Mechanistically, Agpat4 silencing-induced LPA release from CRC cells and polarized macrophages to an M1-like phenotype through LPA receptors 1 and 3. This M1 activation, characterized by elevated p38/p65 signaling and increased proinflammatory cytokines, promoted the infiltration and activation of CD4+and CD8+T cells in the tumor microenvironment. Modulation of the Agpat4/LPA/p38/p65 axis regulated macrophage polarization, T-cell activity and CRC progression. Notably, combined therapy with LPA and regular chemotherapy drugs synergistically suppressed CRC development. Taken together, our results showed that the Agpat4/LPA axis in CRC cells regulated p38/p65 signaling-dependent macrophage polarization, T-cell activation, and CRC progression. The Agpat4/LPA/p38/p65 axis might represent a potential target for therapy in the clinic.