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High-grade serous ovarian cancer (HGSOC) represents the major histological type of ovarian cancer, and the lack of effective screening tools and early detection methods significantly contributes to the poor prognosis of HGSOC. Currently, there are no reliable diagnostic biomarkers for HGSOC. In this study, we performed liquid chromatography data-independent acquisition tandem mass spectrometry (MS) on depleted serum samples from 26 HGSOC cases and 24 healthy controls (HCs) to discover potential HGSOC diagnostic biomarkers. A total of 1,847 proteins were identified across all samples, among which 116 proteins showed differential expressions between HGSOC patients and HCs. Network modeling showed activations of coagulation and complement cascades, platelet activation and aggregation, neutrophil extracellular trap formation, toll-like receptor 4, insulin-like growth factor, and transforming growth factor β signaling, as well as suppression of lipoprotein assembly and Fc gamma receptor activation in HGSOC. Based on the network model, we prioritized 28 biomarker candidates and validated 18 of them using targeted MS assays in an independent cohort. Predictive modeling showed a sensitivity of 1 and a specificity of 0.91 in the validation cohort. Finally, in vitro functional assays on four potential biomarkers (FGA, VWF, ARHGDIB, and SERPINF2) suggested that they may play an important role in cancer cell proliferation and migration in HGSOC. All raw data were deposited in PRIDE (PXD033169).

e17564 Background: Ovarian cancer (OC) is one of the most common causes of cancer-related death among women worldwide. High-grade serous ovarian cancer (HGSOC) represents the major OC histological type, and challenges associated with its early detection and prediction of clinical outcomes significantly contribute to the high prevalence and poor prognosis of OC. Lack of reliable biomarkers further exacerbates the low survival rate of patients with HGSOC. Methods: In this study, we performed liquid chromatography data independent acquisition tandem-mass spectrometry (LC-DIA-MS/MS) experiments on depleted serum samples [26 HGSOC cases, 24 healthy controls (HCs)] to identify potential diagnostic and prognostic biomarkers for HGSOC. Results: A total of 1,148 proteins were identified in all samples combined, representing one of the largest quantifications in the serum proteome of OC to date. Among them, 122 proteins showed differential expressions between the serum proteome of HGSOC patients and HCs, including 109 up- and 14 down-regulated proteins in HGSOC. These potential diagnostic biomarkers were involved in the pathways related to immune response, TGF- β and IGF signaling, and lipid metabolism. Moreover, we performed Kaplan-Meier survival analysis on the HGSOC patients with and without recurrence, and identified several potential prognostic biomarkers highly associated with progression free survival (PFS). Using independent cohort samples, we validated the expression levels of HGSOC serum biomarker candidates using targeted proteomics approaches (MRM and PRM). In vitro functional assays revealed that some of these biomarkers may play an essential role in cancer cell migration and proliferation in HGSOC. Conclusions: In summary, our LC-DIA-MS/MS analysis of the HGSOC serum proteome successfully identified novel diagnostic and prognostic biomarkers for HGSOC, some of which were experimentally shown to have functional relevance to the pathophysiology of OC.

Established fear memory becomes vulnerable to disruption after memory retrieval and extinction; this labile state is critical for inhibiting the return of fear memory. However, the labile state has a very narrow time window after retrieval, and underlying molecular mechanisms are not well known. To that end, we isolated the hippocampus immediately after fear memory retrieval and performed proteomics. We identified Neurobeachin (NBEA), an autism-related regulator of synaptic protein trafficking, to be upregulated after contextual fear memory retrieval. NBEA protein expression was rapid and transient after fear memory retrieval at the synapse. Nbea mRNA was enriched at the synapses, and the rapid induction of NBEA expression was blocked by inhibition of the mammalian target of rapamycin (mTOR)-dependent signaling pathway. Mice with cornu ammonis 1 (CA1)-specific Nbea shRNA knockdown showed normal fear acquisition and contextual fear memory but impaired extinction, suggesting an important role of Nbea in fear memory extinction processes. Consistently, Nbea heterozygotes showed normal fear acquisition and fear memory recall but showed impairment in extinction. Our data suggest that NBEA is necessary either for induction of memory lability or for the physiological process of memory extinction.