Comprehensive Identification of the Human Secretome as Potential Indicators in Treatment Outcome of HPV-Positive and -Negative Cervical Cancer Patients

Abstract

<b><i>Background:</i></b> The aim of this work was to explore the novel and promising biomarkers for the diagnosis and prognosis of cervical cancer patients. <b><i>Methods:</i></b> The secretome of primary cervical tissues was extracted and then determined by the LC-MS/MS assay. The level of screened targets was confirmed using the RT-PCR and ELISA in cervical cancer tissue samples. The median expression level of certain targets was used as a cutoff value to divide the patients into 2 groups, and then the patients were followed up. The predictive abilities of the targets on the prognosis were further studied. <b><i>Results:</i></b> LC-MS/MS, together with bioinformatic analysis, demonstrated that totally 95 targets were dysregulated in cervical cancer. Among them, ECM2, KLK6, and MASP1 were increased in cervical cancer in a stage-dependent manner, whereas FGA was negatively associated with the stage of cervical cancers. Overall survival (OS) and disease-free survival (DFS) rates were significantly decreased in the KLK6 high group, whereas little difference was found between the high and low groups of other 3 cases. Univariate analysis of the 5-year OS and DFS revealed a significantly worse outcome for patients with KLK6 high tumors. In multivariate analysis, KLK6 remained a highly significant prognostic marker for OS and DFS. Combined survival analysis of KLK6 expression and the HPV infection revealed that KLK6^highHPV⁽⁻⁾ predicted the most poor OS rate and the KLK6^lowHPV⁽⁺⁾ group showed the best prognosis. <b><i>Conclusion:</i></b> Through the secretome analysis, we identified a series of secreted proteins differentially expressed in the clinical cancer, among which KLK6 has the potential to become a promising biomarker for the diagnosis and prognosis of cervical cancer patients.