J Cancer 2019; 10(24):6025-6036. doi:10.7150/jca.34886

Research Paper

Downregulated Salt-inducible Kinase 3 Expression Promotes Chemoresistance in Serous Ovarian Cancer via the ATP‐binding Cassette Protein ABCG2

Yu-Ling Liang1*, Chin-Han Wu1,2*, Chieh-Yi Kang3, Chang-Ni Lin1, Neng-Yao Shih4, Sheng-Hsiang Lin5, Yeong-Chang Chen4, Keng-Fu Hsu1,5✉

1. Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan;
2. Department of Dental Technology, Shu Zen Junior College of Medicine and Management;
3. Department of Obstetrics and Gynecology, Chi Mei Medical Center, Yongkang, Tainan, Taiwan;
4. National Institute of Cancer Research, National Health Research Institutes;
5. Graduate Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
*These authors contributed equally to this work

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Citation:
Liang YL, Wu CH, Kang CY, Lin CN, Shih NY, Lin SH, Chen YC, Hsu KF. Downregulated Salt-inducible Kinase 3 Expression Promotes Chemoresistance in Serous Ovarian Cancer via the ATP‐binding Cassette Protein ABCG2. J Cancer 2019; 10(24):6025-6036. doi:10.7150/jca.34886. Available from http://www.jcancer.org/v10p6025.htm

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Abstract

Background: Epithelial ovarian cancer (EOC) has a high tumor-associated mortality rate among gynecological cancers. Although CA125 is a well-studied biomarker for ovarian cancer, it is also elevated under numerous conditions, resulting in decreased specificity. Recently, we identified a novel tumor-associated antigen, salt-inducible kinase 3 (SIK3), during tumorigenesis in ovarian cancer. However, the association between SIK3 expression and patient outcomes in ovarian cancer remains unclear.

Materials and Methods: We collected EOC samples from 204 patients and examined tumor SIK3 expression by immunohistochemistry (IHC) and CA125 expression in tumors and serum. The expression levels of SIK3 and CA125 were correlated with patient survival. SIK3 expression was silenced with SIK3-specific shRNAs to investigate the possible mechanisms related to chemoresistance in serous-type ovarian cancer cell lines OVCAR4 and SKOV3.

Results: In advanced-stage serous ovarian cancer, patients with low SIK3 expression have poorer overall survival (OS) and progression-free survival (PFS) than patients with high SIK3 expression. Ovarian cancer cells with SIK3 knockdown display increased chemoresistance to Taxol plus cisplatin treatment, which is associated with the upregulation of the ABCG2 transporter. In addition, in serous ovarian cancer, SIK3 expression is inversely correlated to ABCG2 expression, and patients with low SIK3 and high ABCG2 expression have worse prognosis than patients with high SIK3 and low ABCG2 expression.

Conclusion: Our results demonstrated that serous EOC patients with low SIK3 expression have poor prognosis, which is associated with chemoresistance mediated by ABCG2 upregulation. SIK3 and ABCG2 expression levels may be potential prognostic markers to predict the outcome in serous EOC patients.

Keywords: ovarian cancer, SIK3, ABCG2, chemoresistance