PAF signaling axis functions as biomarker or target for esophageal squamous cell carcinoma diagnosis or treatment

Abstract

Dysregulated lipid metabolism is one of the most extinguishing metabolic hallmarks, and contributes to tumorigenesis and tumor malignancy. Platelet-activating factor (PAF), the lipid metabolite, serves as an inflammatory stimulator to induce the aggressive progression of esophageal squamous cell carcinoma (ESCC). However, whether PAF and its downstream signaling axis can function as biomarker or therapeutic target for ESCC diagnosis or treatment are still unclear. In this study, we found that plasma PAF level can reflect the lymph node (LN) metastasis status of ESCC patients. Importantly, results from Olink assay showed that several cytokines in plasma, such as interleukin-8 (IL-8), C-X-C motif chemokine ligand 1 (CXCL1), CXCL5, or CXCL11 were positively related with the LN metastasis status of ESCC patients, the expression of these cytokines was also tightly correlated with that of PAF in the plasma from LN metastatic ESCC patients. Results from RNA-seq in ESCC cell lines and immunohistochemistry (IHC) in clinical ESCC samples showed that PAF signaling effectively induced the expression of these cytokines and some tumor-promoting molecules in ESCC. Therapeutically, ginkgetin, a natural biflavonoid isolated from Ginkgo biloba L, inhibited the PAF-mediated Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) activation, the expression of downstream inflammatory cytokines, glycolysis- and tumor-progression related molecules, and the malignancy of tumor cells both in vitro and in vivo, but generated barely significant toxicity towards the normal tissues of xenografted animals. Present study has illustrated that PAF can serve as biomarker for evaluation of ESCC LN metastasis, and ginkgetin could exert excellent antitumor effect on ESCC cells via suppressing PAF axis-controlled signaling pathways.