甲酰肽受体1（FPR1）在神经母细胞瘤肿瘤发生中的作用。

The role of formyl peptide receptor 1 (FPR1) in neuroblastoma tumorigenesis.

作者信息

Snapkov Igor, Öqvist Carl Otto, Figenschau Yngve, Kogner Per, Johnsen John Inge, Sveinbjørnsson Baldur

机构信息

Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.

Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

出版信息

BMC Cancer. 2016 Jul 18;16:490. doi: 10.1186/s12885-016-2545-1.

BACKGROUND

Formyl peptide receptor 1 (FPR1) is a G protein-coupled receptor mainly expressed by the cells of myeloid origin, where it mediates the innate immune response to bacterial formylated peptides. High expression of FPR1 has been detected in various cancers but the function of FPR1 in tumorigenesis is poorly understood.

METHODS

Expression of FPR1 in neuroblastoma cell lines and primary tumors was studied using RT-PCR, western blotting, immunofluorescence and immunohistochemistry. Calcium mobilization assays and western blots with phospho-specific antibodies were used to assess the functional activity of FPR1 in neuroblastoma. The tumorigenic capacity of FPR1 was assessed by xenografting of neuroblastoma cells expressing inducible FPR1 shRNA, FPR1 cDNA or control shRNA in nude mice.

RESULTS

FPR1 is expressed in neuroblastoma primary tumors and cell lines. High expression of FPR1 corresponds with high-risk disease and poor patient survival. Stimulation of FPR1 in neuroblastoma cells using fMLP, a selective FPR1 agonist, induced intracellular calcium mobilization and activation of MAPK/Erk, PI3K/Akt and P38-MAPK signal transduction pathways that were inhibited by using Cyclosporin H, a selective receptor antagonist for FPR1. shRNA knock-down of FPR1 in neuroblastoma cells conferred a delayed xenograft tumor development in nude mice, whereas an ectopic overexpression of FPR1 promoted augmented tumorigenesis in nude mice.

CONCLUSION

Our data demonstrate that FPR1 is involved in neuroblastoma development and could represent a therapy option for the treatment of neuroblastoma.

背景

甲酰肽受体1（FPR1）是一种G蛋白偶联受体，主要由髓系来源的细胞表达，在其中介导对细菌甲酰化肽的先天免疫反应。已在多种癌症中检测到FPR1的高表达，但对FPR1在肿瘤发生中的功能了解甚少。

方法

使用逆转录聚合酶链反应（RT-PCR）、蛋白质免疫印迹法、免疫荧光法和免疫组织化学法研究FPR1在神经母细胞瘤细胞系和原发性肿瘤中的表达。使用钙动员试验和磷酸化特异性抗体的蛋白质免疫印迹法评估FPR1在神经母细胞瘤中的功能活性。通过将表达可诱导FPR1短发夹RNA（shRNA）、FPR1互补DNA（cDNA）或对照shRNA的神经母细胞瘤细胞移植到裸鼠体内来评估FPR1的致瘤能力。

结果

FPR1在神经母细胞瘤原发性肿瘤和细胞系中表达。FPR1的高表达与高危疾病和患者的不良生存相关。使用选择性FPR1激动剂N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸（fMLP）刺激神经母细胞瘤细胞中的FPR1可诱导细胞内钙动员以及丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/Erk）、磷脂酰肌醇-3-激酶/蛋白激酶B（PI3K/Akt）和P38丝裂原活化蛋白激酶信号转导途径的激活，而使用FPR1的选择性受体拮抗剂环孢菌素H可抑制这些途径。在神经母细胞瘤细胞中敲低FPR1的shRNA可使裸鼠体内异种移植肿瘤的发育延迟，而FPR1的异位过表达则促进裸鼠体内肿瘤发生增加。