Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI) - University of Naples Federico II, Naples, Italy.
Department of Molecular Medicine and Medical Biotechnology - University of Naples and CNR Institute of Experimental Oncology and Endocrinology (IEOS), Naples, Italy.
Oncogene. 2015 Jul;34(29):3826-38. doi: 10.1038/onc.2014.309. Epub 2014 Sep 29.
N-formyl peptide receptors (FPR1, FPR2 and FPR3) are involved in innate immunity, inflammation and cancer. FPR expression, initially described in immune cells, was later observed in non-hematopoietic cell populations and tissues. Several studies suggested a role for FPRs in the progression of various tumor histotypes, including gastric cancer (GC), for which a positive association with a specific FPR1 polymorphism has recently been described. We previously showed that FPRs are expressed on gastric epithelium and are required for wound repair and restitution of barrier integrity. Here we assess the role of FPRs in GC. We characterized the functions of FPRs in GC epithelial cells (MKN28, AGS and MKN45) cultured in vitro by assessing migration, proliferation, resistance to apoptosis and activation of the epithelial-to-mesenchymal transition. Activation of each FPR induced the epithelial-to-mesenchymal transition, proliferation, resistance to apoptosis and migration of GC cells in culture. Blocking compounds or RNA interference of each FPR reverted these effects. We also defined the in vivo tumorigenic potential of GC epithelial cells silenced for FPRs by xenograft experiments in immunocompromised mice. Interestingly, FPR1 silencing in GC cells (shFPR1) significantly enhanced xenograft growth with respect to shCTR, shFPR2 and shFPR3 xenografts, because of augmented vessel density and cell proliferation. Accordingly, HIF-1α and VEGF mRNA levels were higher in shFPR1 xenografts than in controls. Moreover, the in vitro production of proangiogenic factors in response to FPR2/3 agonists (WKYMVm, LL-37, uPA, uPAR84-95, AnxA1) or to other proinflammatory mediators (IL-1α) was higher in shFPR1 GC cells than in shCTR, shFPR2 and shFPR3 cells, suggesting that FPR1 functions as an inhibitor of CG angiogenesis. Thus, we propose that FPR1 stimulation may represent a novel therapeutic approach to counteract tumor angiogenesis.
N-甲酰肽受体（FPR1、FPR2 和 FPR3）参与先天免疫、炎症和癌症。最初在免疫细胞中描述的 FPR 表达后来在非造血细胞群体和组织中观察到。几项研究表明 FPR 在各种肿瘤组织类型的进展中起作用，包括胃癌（GC），最近描述了 FPR1 特定多态性与 GC 的正相关性。我们之前表明 FPR 在胃上皮细胞中表达，并且是伤口修复和屏障完整性恢复所必需的。在这里，我们评估了 FPR 在 GC 中的作用。我们通过评估体外培养的 GC 上皮细胞（MKN28、AGS 和 MKN45）的迁移、增殖、抗凋亡和上皮-间质转化的激活来表征 FPR 在 GC 中的功能。每种 FPR 的激活都诱导 GC 细胞在培养中发生上皮-间质转化、增殖、抗凋亡和迁移。每种 FPR 的阻断化合物或 RNA 干扰都逆转了这些作用。我们还通过免疫缺陷小鼠的异种移植实验定义了沉默 FPR 的 GC 上皮细胞的体内致瘤潜能。有趣的是，与 shCTR、shFPR2 和 shFPR3 异种移植物相比，GC 细胞中 FPR1 的沉默（shFPR1）显著增强了异种移植物的生长，因为血管密度和细胞增殖增加。因此，与对照相比，shFPR1 异种移植物中的 HIF-1α 和 VEGF mRNA 水平更高。此外，与 FPR2/3 激动剂（WKYMVm、LL-37、uPA、uPAR84-95、AnxA1）或其他促炎介质（IL-1α）反应时，shFPR1 GC 细胞体外产生的促血管生成因子高于 shCTR、shFPR2 和 shFPR3 细胞，这表明 FPR1 作为 CG 血管生成的抑制剂发挥作用。因此，我们提出刺激 FPR1 可能代表一种新的治疗方法来对抗肿瘤血管生成。
