Asparagine Synthetase and Filamin A Have Different Roles in Ovarian Cancer

Liang Zeng; Qiong Wang; Congmin Gu; Li Yuan; Xiaohui Xie; Lijuan He; Kai Chen; Pingping Tan; Lei Xue; Sanqian Huang; Kun Shi

doi:10.3389/fonc.2019.01072

Asparagine Synthetase and Filamin A Have Different Roles in Ovarian Cancer

Front Oncol. 2019 Oct 18:9:1072. doi: 10.3389/fonc.2019.01072. eCollection 2019.

Authors

Liang Zeng¹, Qiong Wang^{2

3}, Congmin Gu¹, Li Yuan¹, Xiaohui Xie², Lijuan He¹, Kai Chen¹, Pingping Tan⁴, Lei Xue⁴, Sanqian Huang⁴, Kun Shi²

Affiliations

¹ Department of Pathology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
² Department of Gynecology and Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
³ Division of Uterine Vascular Biology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China.
⁴ Department of Pathology, Hunan Cancer Hospital & the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.

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; ASNS^high and FLNA^low) and cisplatin-resistant (CR; ASNS^low and FLNA^high) 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.

Keywords: ASNS; FLNA; cisplatin-resistance; high-grade ovarian serous carcinoma; iTRAQ; low-grade ovarian serous carcinoma; tumor growth.