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Identification of salt-inducible kinase 3 as a novel tumor antigen associated with tumorigenesis of ovarian cancer

Oncogene volume 30, pages 3570–3584 (2011)Cite this article

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Abstract

Existence of humoral immunity has been previously demonstrated in malignant ascitic fluids. However, only a limited number of immunogenic tumor-associated antigens (TAAs) were identified, and few of which are associated with ovarian cancer. Here, we identified salt-inducible kinase 3 (SIK3) as a TAA through screening of a random peptide library in the phage display system. Overexpression of SIK3 markedly promoted cell proliferation, attenuated p21Waf/Cip1 and p27Kip expressions in low-grade OVCAR3 cells, and permitted the cells to grow in mice. Decrease in SIK3 expression in high-grade SK-OV3 cells consistently demonstrated its tumorigenic potency by modulating the protein levels of cell cycle regulators. When the expressions of SIK3 and CA125 were compared in cancer tissues, immunohistochemical (IHC) studies indicated that cytoplasm-localized SIK3 was highly expressed in 55% of the ovarian cancer samples. In contrast, it was rarely detected in adenomyosis, leiomyoma and normal ovary tissues, showing its higher specificity (97%) to CA125 (65%) in ovarian cancer. Moreover, experiments using pharmacological inhibitors to block SIK3-induced p21Waf/Cip1 expression revealed that activation of c-Src and phosphoinositide-3-kinase were critically required for its biological activity, suggesting that they are the downstream signaling mediators of SIK3. These data were further supported by IHC studies, showing coexpression of c-Src with SIK3 in 85% of the ovarian tumor samples stained positive for SIK3. Collectively, our findings indicate that SIK3 is a novel ovarian TAA. Overexpression of SIK3 promotes G1/S cell cycle progression, bestows survival advantages to cancer cells for growth and correlates the clinicopathological conditions of patients with ovarian cancer.

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Acknowledgements

This work was partially supported by the Intramural Research Grant of the National Health Research Institutes, the National Research Program for Genomic Medicine Grant from the Department of Health, Executive Yuan, Taiwan, DOH97-TD-G-111-022 (NYS), and by the National Science Council Grants of Taiwan, NSC 99-2320-B-400-011-MY3 (NYS), NSC 96-2314-B-038-022 (SJL), NSC 97-2314-B-038-004-MY3 (SJL), as well as NSC 96-2320-B-038-005/NSC 97-2320-B-038-012-MY2 (YYY). We are also grateful to Dr Nagase from the Kazusa DNA Research Institute for kindly providing the FJ10213 plasmid to facilitate the SIK3 study, and thank National Research Program for Genomic Medicine, Taiwan (National Clinical Core, NSC-95-3112-B-001-010 and National Genotyping Core, NSC-95-3112-B-001-011) for supply of interfering small hairpin RNA plasmids.

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Author notes

  1. Y-C Lee

    Present address: 11Current address: The Genomic Research Center, Academia Sinica, Taipei 115, Taiwan.,

  2. Y-Y Yang, Y-C Lee and K-C Chao: These authors contributed equally to this work.

  3. S-J Leu and N-Y Shih: S-J Leu and N-Y Shih co-correspond to this work.

Authors and Affiliations

  1. Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, Taipei, Taiwan

    S Charoenfuprasert & S-J Leu

  2. Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    S Charoenfuprasert & S-J Leu

  3. School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

    Y-Y Yang & Y-C Lee

  4. Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan

    K-C Chao

  5. Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan

    P-Y Chu

  6. Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan

    C-R Lai

  7. Department of Obstetrics and Gynecology, National Cheng Kung University, Tainan, Taiwan

    K-F Hsu

  8. Department of Pathology, National Cheng Kung University, Tainan, Taiwan

    K-C Chang

  9. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan

    S Charoenfuprasert, Y-C Chen, L-T Chen, J-Y Chang & N-Y Shih

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  1. S Charoenfuprasert
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Correspondence to S-J Leu or N-Y Shih.

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Charoenfuprasert, S., Yang, YY., Lee, YC. et al. Identification of salt-inducible kinase 3 as a novel tumor antigen associated with tumorigenesis of ovarian cancer. Oncogene 30, 3570–3584 (2011). https://doi.org/10.1038/onc.2011.77

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