Abstract
Early-stage ovarian serous carcinoma is usually difficult to detect in clinical practice. The profiling of protein expression in high-grade serous carcinoma (HGSC) and low-grade serous carcinoma (LGSC) would provide important information for diagnoses and chemotherapy. Here, we performed proteomic profiling of specimens from 13 HGSC and 7 LGSC patients by iTRAQ. A total of 323 proteins that were differentially expressed were identified. After immunohistochemical confirmation of expressed proteins in 166 clinical tissues, asparagine synthetase (ASNS) and filamin A (FLNA) were selected for further functional study. Cisplatin-sensitive (CS; ASNShigh and FLNAlow) and cisplatin-resistant (CR; ASNSlow and FLNAhigh) SKOV3 and OVCAR3 ovarian cancer cell lines were used for subsequent in vitro and in vivo experiments. Notably, ASNS overexpression (ASNS+) or FLNA knockdown (shFLNA) enabled cisplatin-induced apoptosis and autophagy in CR cells. However, ASNS+ and shFLNA promoted and attenuated tumor growth, respectively. In CS cells, ASNS knockdown (shASNS) attenuated clonogenicity, cell proliferation, and the epithelial–mesenchymal transition, whereas FLNA overexpression (FLNA+) protected cells from cisplatin. In vivo, cisplatin resistance was attenuated in mice xenografted with ASNS+, shFLNA, or ASNS+-shFLNA CR cells, whereas xenografts of shASNS or FLNA+ CS cells exhibited resistance to cisplatin. Clinically, all HGSC patients (83/83) responded to cisplatin, while 6 in 41 LGSC patients exhibited cisplatin resistance. These findings identify ASNS and FLNA as distinct biomarkers for HGSC and LGSC, which may have potential value in the prognosis and clinical treatment of serous carcinoma.
Highlights
Ovarian cancer has the highest mortality rate of all female genital tract cancers [1] and poses a serious threat to women’s health
Each specimen was divided into 3 parts: one part was for rapid diagnosis by frozen section during the operation, one part was stored in liquid nitrogen for isobaric tags for relative and absolute quantitation (iTRAQ) proteomic examination, and one part was formaldehyde-fixed and embedded in paraffin for HE staining to identify pathological type and for immunohistochemistry (IHC) staining to confirm in situ expression of the differentially expressed proteins
The high-grade serous carcinoma (HGSC) samples were formed into groups of 113 and 114, while the 7 low-grade serous carcinoma (LGSC) samples were formed into groups of 119 and 121
Summary
Ovarian cancer has the highest mortality rate of all female genital tract cancers [1] and poses a serious threat to women’s health. LGSCs originate from adenofibromas or borderline tumors and are charaterized by KRAS or BRAF mutations but lack TP53 mutations [3, 6] They present low-grade nuclei with few mitotic figures and usually develop slowly with slow stepwise invasive transformation [3]. HGSCs appear to originate from intraepithelial carcinoma in the fallopian tube and are characterized by TP53 mutations, BRCA germline mutations in hereditary tumors, and the absence of KRAS or BRAF mutations [3, 4, 6]. Their differential protein profile and function, which is responsible for their phenotypic difference, are rarely reported
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