Abstract
Objective: High-risk human papillomavirus (HR-HPV) is the main etiological factor for cervical cancer. Accumulating evidence has suggested that the active role of metabolites in the initiation and progression of cancers. This study was to explore the metabolic profiles of HR-HPV infection and their potential functions in cervical cancer.Methods: Non-targeted metabolomics approach was used to detect metabolic alterations in the plasma obtained from HPV-16 positive (HPV16 (+)), HPV-18 positive (HPV18 (+)) and HPV negative (CTL) individuals, followed by CCK8 experiment to detect the effect of different metabolites on the proliferation of Hela and GH354. A cell migration test then verified significant metabolites on the migration of Hela and GH354. Q RT-qPCR and western blot were used to detect malignant progression related mRNA and protein expression levels of cervical cancer.Results: HR-HPV groups shared 24 dysregulated metabolites (such as amino acids, ceramides, glycerophosphocholines). Further experiments showed ceramide species, including C8 inhibits cervical cancer cells proliferation and migration in vitro. In contrast, C12 significantly enhanced cervical cancer cells proliferation and migration in vitro. Protein and mRNA expressions indicated C8 and C12 were related to the malignant behavior of cervical cancer in vitro. The underlying mechanism demonstrated that C8 intervention inhibited proliferation and migration in cervical cancer cells via the MAPK/JNK signaling pathway, while C12 intervention promoted proliferation and migration in cervical cancer cells via the MAPK/ERK signaling pathway. These findings may contribute to the treatment of HR-HPV-induced cervical cancer by intervening in its initiation and progression.Conclusion: Our study shed some light on how metabolites influenced the relationship between HR-HPV oncogenic capability and metabolic phenotype change and identify species C8 and C12 as critical lipid metabolites that modulate cervical cancer cell’s function.